Fast-acting plant-based medicinal compounds and nutritional supplements

ABSTRACT

Plant-based medicinal compounds or nutritional supplements in various carrier combinations are described. The carriers can include N-acylated fatty amino acids, penetration enhancers, and/or various other beneficial carriers. The plant-based composition/carrier combinations can create administration benefits.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application claims priority to U.S. Provisional Patent ApplicationNo. 62/326,490 filed Apr. 22, 2016 and to U.S. Provisional PatentApplication No. 62/429,544 filed Dec. 2, 2016, the entire contents ofeach of which are incorporated by reference herein.

FIELD OF THE DISCLOSURE

The current disclosure provides fast-acting plant-based medicinalcompounds or nutritional supplements in various carrier combinations.The carriers can include N-acylated fatty amino acids, penetrationenhancers, and/or various other beneficial carriers. The plant-basedcomposition/carrier combinations can create administration benefitsfollowing oral administration.

BACKGROUND OF THE DISCLOSURE

Historically, the plant world has been the most important source ofmedicinal agents for the treatment of human and animal disease, and foruse as preventative agents in maintaining good health. However, for atleast the last 150 years, Western medicine has been dominated bysynthetic chemical agents.

It is now being increasingly recognized, however, that many plants andplant extracts are highly effective agents for the prevention andtreatment of disease. A single plant can possess a large number ofpharmaceutically active agents, and extracts obtained therefrom canexert their activities on a variety of physiologic processes, increasingthe range of the desired therapeutic effect.

As one example, U.S. Publication No. 2015/0050373 describes use ofplants from the Calophyllum genus to treat metabolic disorders.Calophyllum is a flowering plant genus of around 180-200 species oftropical evergreen trees. The Calophyllum genus includes foursubcategories: Calophyllum brasiliense, Calophyllum caledonicum,Calophyllum inophyllum and Calophyllum soulattri. Calophylluminophyllum, is a medium to large sized evergreen tree that averages25-65 feet in height. Different medicinal uses of this plant have beenreported in the literature, for example, decoction of the bark of thisplant treats internal hemorrhages. The oil extracted from Calophylluminophyllum seeds is used to treat rheumatoid arthritis or jointdisorders; itching; eczema; pimples appearing on head; eye diseases; andkidney failure.

U.S. Publication No. 2014/0193345 describes use of the plants Uncariatomentosa, Thymus vulgaris, Matricaria recutita, Salix alba, Calendulaofficinalis, Usnea barbata, Ligusticum porterii-osha, Gaultheriaprocumbens, Camellia sinensis, Vaccinium myrtillus, Melissa officinalis,Allium sativum, Camellia sinensis and Krameria triandra to treat mucosallesions.

U.S. Publication No. 2010/0068297 describes use of the plants Punicagranatum, Viburnum plicatum, Camellia sinensis, and Acer spp. asantimicrobials.

Numerous medical uses have also been identified for the cannabis plant.For example, delta-9-tetrahydrocannabinol (THC, also referred to asDronabinol), an extract of the cannabis plant has been formulated insesame oil for oral delivery. THC exhibits complex effects on thecentral nervous system (CNS), including central sympathomimeticactivity. THC has been shown to have a marked appetite stimulant effectand has been used in the treatment of AIDS-related anorexia. THCdemonstrates effects on appetite, mood, cognition, memory andperception. Furthermore, the drug has anti-emetic properties and is usedto control nausea and vomiting associated with cancer chemotherapy.These effects appear to be dose related.

THC's efficacy in pain treatment has been described in Pharm. J. 259,104, 1997 and in Pharm. Sci. 3, 546, 1997. Nabilone, a syntheticcannabinoid has also been reported to be an anti-emetic and anxiolytic,and also useful for treating pain of various etiologies such as multiplesclerosis (MS), peripheral neuropathy and spinal injuries (Lancet, 1995,345, 579, Pharm. J. 259, 104, 1997; Baker & Pryce, Expert Opin InvestigDrugs. 2003 April; 12(4):561-7)). THC has also been reported to beuseful in the treatment of AIDS (J. Pain. Symptom Manage. 1995, 10,89-97) when given orally.

Another cannabinoid with well-documented health benefits is cannabidiol(CBD). In contrast to THC, CBD does not exert psychoactive effects. CBDis reported to have antidepressant (Zanelati T, et al. Journal ofPharmacology. 2010. 159(1):122-8;), anti-anxiety (Resstel B M, et al. BrJ Pharmacol. 2009. 156(1):181-188), anti-inflammatory (Vuolo F, et al.Mediators of Inflammation. 2015. 538670), and neuroprotective effects(Campos A C, et al. Pharmacol Res. 2016. 112:119-127).

Additional uses for the cannabis plant include treatment of addiction(De Vries, et al., Psychopharmacology (Berl). 2003 July;168(1-2):164-9); ADHD (O'Connell and Ché, Harm Reduction Journal. 2007;4:16); alcoholism (Basavarajappa & Hungund, Alcohol. 2005January-February; 40(1):15-24); Alzheimer's disease (Eubanks et al., MolPharm. 2006 November-December; 3(6):773-7); amyotrophic lateralsclerosis (ALS) (Raman et al., Amyotroph Lateral Scler Other MotorNeuron Disord. 2004 March; 5(1):33-9); anxiety (The British Journal ofPsychiatry February 2001, 178 (2) 107-115); asthma (Tashkin et al.,American Review of Respiratory Disease, 1975; 112, 377); auto-immunediseases (Lyman et al., J Neuroimmunol. 1989 June; 23(1):73-81);bacterial infections (Nissen et al., Fitoterapia. 2010 July;81(5):413-9); bone loss (Bab et al., Ann Med. 2009; 41(8):560-7); braininjury/stroke (Shohami et al., Br J Pharmacol. 2011 August;163(7):1402-10); cancer (Guindon & Hohmann, Br J Pharmacol. 2011 August;163(7):1447-63); heart disease (Walsh et al., Br J Pharmacol. 2010 July;160(5):1234-42); Huntington's disease (Lastres-Becker et al., JNeurochem. 2003 March; 84(5):1097-109); inflammation (AAPS J. 2009March; 11(1): 109-119); Parkinson's disease (Sieradzan et al.,Neurology. 2001 Dec. 11; 57(11):2108-11); and psoriasis (TrendsPharmacol Sci. 2009 August; 30(8): 411-420).

Additional documented uses for the cannabis plant include treatingacquired hypothyroidism, acute gastritis, agoraphobia, ankyloses,arthritis, Asperger's syndrome, atherosclerosis, autism, bipolardisorder, blood disorders, cachexia, carpal tunnel syndrome, cerebralpalsy, cervical disk disease, cervicobrachial syndrome, chronic fatiguesyndrome, chronic pain, cluster headache, conjunctivitis, Crohn'sdisease, cystic fibrosis, depression, dermatitis, diabetes, dystonia,eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungalinfection, gastrointestinal disorders, glaucoma, glioma, Grave'sdisease, hepatitis, herpes, hypertension, impotence, incontinence,infant mortality, inflammatory bowel disease (IBD), insomnia, liverfibrosis, mad cow disease, menopause, migraine headaches, motionsickness, MRSA, muscular dystrophy, nail patella syndrome,neuroinflammation, nicotine addiction, obesity, obsessive compulsivedisorder (OCD), pancreatitis, panic disorder, periodontal disease,phantom limb pain, poison ivy allergy, premenstrual syndrome (PMS),proximal myotonic myopathy, post-traumatic stress disorder (PTSD),Raynaud's disease, restless leg syndrome, schizophrenia, scleroderma,septic shock, shingles herpes zoster), sickle cell disease, seizures,sleep apnea, sleep disorders, stress, stuttering, temporomandibularjoint disorder (TMJ), tension headaches, tinnitus, Tourette's syndrome,traumatic memories, wasting syndrome, and withdrawal.

Despite the numerous benefits associated with plant-based compounds andnutritional supplements, when administered in oral form, their onset ofaction can be slow, which can detract from their usefulness in someinstances. For example, after oral administration, THC has an onset ofaction of fifteen minutes at the very earliest to 1.5 hours and a peakeffect at 2-4 hours. The duration of action for psychoactive effects is4-6 hours, but the appetite stimulant effect may continue for 24 hoursor longer after administration. THC is almost completely absorbed(90-95%) after single oral doses. However, due to a combined effect offirst pass hepatic metabolism and poor aqueous solubility (THC watersolubility is 2.8 mg/L), only 10-20% of the administered dose reachesthe systemic circulation. Therefore, oral consumption of cannabis ischaracterized by low bioavailability of cannabinoids, and slow onset ofaction. Thus, as this one example provides, there is room forimprovement in the oral administration of plant-based compounds andnutritional supplements.

SUMMARY OF THE DISCLOSURE

The current disclosure provides fast-acting plant-based medicinalcompounds and nutritional supplements (collectively, plant-basedcompositions) formulated for oral delivery. By providing fast-actingdelivery, physiological benefits are observed earlier increasing theusefulness of these compounds.

The disclosed fast-acting plant-based compositions can create variousadministration benefits in providing therapeutically effective amountsin a variety of conditions. Exemplary administration benefits includeincreased absorption, increased bioavailability, faster onset of action,higher peak concentrations, faster time to peak concentrations, shorterduration of action, increased subjective therapeutic efficacy, andincreased objective therapeutic efficacy.

The fast-acting nature of the plant-based compositions is created byincluding one or more N-acylated fatty amino acids, absorption enhancingagents, and/or various other beneficial carriers, such as surfactants,detergents, azones, pyrrolidones, glycols and bile salts in an oralformulation. In particular embodiments, N-acylated fatty amino acids canbe linear, branched, cyclic, bicyclic, or aromatic including, forexample, 1-50 carbon atoms in an oral formulation. That use ofN-acylated fatty amino acids could provide a fast-acting benefit with aplant-based composition was unexpected given particular aspects ofplant-based components described further herein. For example, theability of N-acylated fatty amino acids to increase absorption ofcompounds is proportional to the water-solubility of a compound. Manyplant-based compounds are not water-soluble and would not have beenexpected to be affected by the presence of an N-acylated fatty aminoacid.

In particular embodiments, the plant-based compositions includeCalophyllum brasiliense, Calophyllum caledonicum, Calophylluminophyllum, Calophyllum soulattri, Uncaria tomentosa, Thymus vulgaris,Matricaria recutita, Salix alba, Calendula officinalis, Usnea barbata,Ligusticum porterii-osha, Gaultheria procumbens, Camellia sinensis,Vaccinium myrtillus, Melissa officinalis, Allium sativum, Camelliasinensis, Krameria triandra, Punica granatum, Viburnum plicatum,Nicotiana tabacum, Duboisia hopwoodii, Asclepias syriaca, Curcuma longa,Cannabis sativa, Cannabis indica, Cannabis ruderalis, and Acer spp., oran extract thereof. In particular embodiments, the plant-basedcompositions include the cannabis plant, or an extract thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A and 1B show an established correlation between water-solubilityand the ability of SNAC to improve a molecule's absorption. FIG. 1Ashows the multiple of improvement from SNAC plotted for cromolyn,vitamin B12, atorvastatin, and ibandronate, along with the aqueoussolubility of each molecule. The plotted data shows a striking fit to alogarithmic trendline (R²=0.998), indicating a logarithmic relationshipbetween the aqueous solubility of each and the extent to which SNACimproves absorption. FIG. 1B plots the aqueous solubility of heparin,acyclovir, rhGH, PTH, MT-II, GLP-1, calcitonin, yy peptide, and THCaccording to the logarithmic trendline derived from FIG. 1A.

FIG. 2 provides exemplary cannabinoid structures.

FIG. 3 provides modified amino acids of compounds I-XXXV.

FIG. 4 provides fatty acid amino acids of formula (a), (b), (c), (d),(e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), and(r), wherein R1 is an alkyl group including 5 to 19 carbon atoms, R2 isH (i.e. hydrogen) or CH3 (i.e. methyl group), and R3 is H; or a salt orthe free acid form thereof.

FIGS. 5A and 5B provide the average results of the study comparing onsetand duration of action of orally administeredcannabis/N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC, “test”)formulation and cannabis (without SNAC, “control”) formulation.

FIGS. 6A-6F provide the results for each individual participant in thestudy comparing onset and duration of action of orally administeredcannabis/N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC, “test”)formulation and cannabis (without SNAC, “control”) formulation.

FIG. 7 shows a comparison of intensity, duration and onset of action oforally administered cannabis formulations with a high SNAC dose (200 mg,“high dose”), a low SNAC dose (100 mg, “low dose”) and no SNAC(“control”).

FIG. 8 shows intensity, duration and onset of action of cannabisformulated with SNAC administered orally (“PO”) compared to cannabisadministered by inhalation (“INH”).

DETAILED DESCRIPTION

Despite the numerous benefits associated with plant-based compounds andnutritional supplements, when administered in oral form, their onset ofaction can be slow, which can detract from their usefulness in someinstances. For example, after oral administration, THC has an onset ofaction of fifteen minutes at the very earliest to 1.5 hours and a peakeffect at 2-4 hours. The duration of action for psychoactive effects is4-6 hours, but the appetite stimulant effect may continue for 24 hoursor longer after administration. THC is almost completely absorbed(90-95%) after single oral doses. However, due to a combined effect offirst pass hepatic metabolism and poor aqueous solubility (THC watersolubility is 2.8 mg/L) only 10-20% of the administered dose reaches thesystemic circulation. Therefore, oral consumption of cannabis ischaracterized by low bioavailability of cannabinoids, and slow onset ofaction. Thus, as this one example provides, there is room forimprovement in the oral administration of plant-based compounds andnutritional supplements.

The current disclosure provides fast-acting plant-based medicinalcompounds and nutritional supplements (collectively, plant-basedcompositions) formulated for oral delivery. By providing fast-actingdelivery, physiological benefits are observed earlier increasing theusefulness of these compounds.

The disclosed fast-acting plant-based compositions can create variousadministration benefits in providing therapeutically effective amountsin a variety of conditions. Exemplary administration benefits includeincreased absorption, increased bioavailability, faster onset of action,higher peak concentrations, faster time to peak concentrations, shorterduration of action, increased subjective therapeutic efficacy, andincreased objective therapeutic efficacy.

The fast-acting nature of the plant-based compositions is created byincluding one or more N-acylated fatty amino acids, absorption enhancingagents, and/or various other beneficial carriers, such as surfactants,detergents, azones, pyrrolidones, glycols and bile salts in an oralformulation. In particular embodiments, N-acylated fatty amino acids canbe linear, branched, cyclic, bicyclic, or aromatic including, forexample, 1-50 carbon atoms in an oral formulation. That use ofN-acylated fatty amino acids could provide a fast-acting benefit with aplant-based composition was unexpected given particular aspects ofplant-based components described further herein. For example, theability of N-acylated fatty amino acids to increase absorption ofcompounds is proportional to the water-solubility of a compound. Manyplant-based compounds are not water-soluble and would not have beenexpected to be affected by the presence of an N-acylated fatty aminoacid.

Molecules that have been shown to have improved absorption whenco-administered with an N-acylated fatty amino acid (e.g., SNAC) includewater-soluble molecules such as cromolyn, vitamin B12), atorvastatin,ibandronate, heparin, acyclovir, recombinant human growth hormone(rhGH), parathyroid hormone 1-34 (PTH 1-34), α-melanotropin (MT-II),GLP-1, calcitonin, and peptide yy.

FIG. 1A shows an established correlation between water-solubility andthe ability of SNAC to improve a molecule's absorption. For cromolyn,vitamin B12, atorvastatin, and ibandronate, published results includearea under the curve (AUC), which is calculated from a time-course ofplasma levels. To quantify the effect of co-administration with SNAC, amultiple of improvement can be calculated by dividing the AUC for amolecule with SNAC by the AUC for the molecule without SNAC. FIG. 1Ashows the multiple of improvement from SNAC plotted for cromolyn,vitamin B12, atorvastatin, and ibandronate, along with the aqueoussolubility of each molecule. The plotted data shows a striking fit to alogarithmic trendline (R²=0.998), indicating a logarithmic relationshipbetween the aqueous solubility of each and the extent to which SNACimproves its absorption.

Heparin, acyclovir, rhGH, PTH, MT-II, GLP-1, calcitonin, and yy peptideare other molecules have been shown to have SNAC-improved absorption, asdemonstrated by Cmax (maximum drug plasma level) and/or Tmax (the timetaken to reach maximum drug plasma level). As shown in FIG. 1B, each ofthese molecules has an aqueous solubility of more than 0.15 mg/ml, andtherefore, the model accurately predicts that SNAC can improve theirabsorption. This result demonstrates that a SNAC-based absorptionimprovement correlates with a molecule's aqueous solubility. FIG. 1Bfurther plots the aqueous solubility of THC (0.0028 mg/ml) to thelogarithmic trendline and SNAC's predicted effect based on the same.Based at least on the foregoing, the results described herein wereunexpected and would not have been reasonably expected by those ofordinary skill in the art.

Aspects of the disclosure are now described in more detail.

The current disclosure provides fast-acting plant-based compositionsincluding vegetable matter and a carrier as an oral formulation.Plant-based compositions refer to plant-based medicinal compounds andplant-based nutritional supplements. Plant-based medicinal compoundsprovide therapeutically-effective amounts to treat a condition, such asthose described in the Background of the Disclosure. Plant-basednutritional supplements claim a benefit related to a classical nutrientdeficiency; describes how the supplement is intended to affect thestructure or function of the human body; characterizes a documentedmechanism by which the supplement acts to maintain such structure orfunction; and/or describes general well-being associated withconsumption of the product. In particular embodiments, a nutritionalsupplement may not claim to diagnose, mitigate, treat, cure, or preventa specific disease or class of diseases.

Plant-based compositions include vegetable matter. Vegetable matter ismatter produced by a plant and includes any whole plant or plant part(e.g., bark, wood, leaves, stems, roots, flowers, fruits, seeds, orparts thereof) and/or exudates or extracts thereof. In particularembodiments, plant-based compositions include botanical products.Botanical products can include plant materials, algae, macroscopicfungi, and/or combinations thereof. In particular embodiments,plant-based compositions include a mixture of various types of vegetablematter. Plant-based compositions can also include materials derived fromvegetable matter including resins, oils, dried flowers, kief, tinctures,infusions, etc. In particular embodiments, the vegetable matter haslittle or no water solubility. In particular embodiments, plant-basedcompositions do not include synthetic, semi-synthetic, orchemically-modified drugs.

In particular embodiments, the plant-based compositions includevegetable matter derived from Calophyllum brasiliense, Calophyllumcaledonicum, Calophyllum inophyllum, Calophyllum soulattri, Uncariatomentosa, Thymus vulgaris, Matricaria recutita, Salix alba, Calendulaofficinalis, Usnea barbata, Ligusticum porterii-osha, Gaultheriaprocumbens, Camellia sinensis, Vaccinium myrtillus, Melissa officinalis,Allium sativum, Camellia sinensis, Krameria triandra, Punica granatum,Viburnum plicatum, Nicotiana tabacum, Duboisia hopwoodii, Asclepiassyriaca, Curcuma longa, Cannabis sativa, Cannabis indica, Cannabisruderalis and/or Acer spp. or an extract thereof.

In particular embodiments, the plant-based compositions includevegetable matter derived from the cannabis plant. The cannabis plantrefers to a flowering plant including the species (or sub-species)Cannabis sativa, Cannabis ruderalis, and Cannabis indica.

Particular extracts of the cannabis plant include cannabinoids.Cannabinoids are a group of cyclic molecules from cannabis plants thatactivate cannabinoid receptors (i.e., CB1 and CB2) in cells. There areat least 85 different cannabinoids that can be isolated from cannabis.Many cannabinoids produced by cannabis plants, such asΔ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD), have very low or nosolubility in water. The most notable cannabinoids are THC and CBD.Additional examples include cannabigerol (CBG), cannabichromene (CBC),cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL),cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin(CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerolmonomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA),Cannabinol propyl variant (CBNV), cannabitriol (CBO),tetrahydrocannabinolic acid (THCA), and tetrahydrocannabivarinic acid(THCVA). See, for example, FIG. 2. Extracts of the cannabis plantsimilarly include flavonoid compounds, terpenes, terpenoid, andsynthetic, semisynthetic or highly purified versions of any suchconstituent.

Components of plant-based compositions can be produced by, e.g.,pulverization, decoction, expression, and extraction of a starting plantproduct. The term “extract” can include all of the many types ofpreparations containing some or all of the active ingredients found inthe relevant plants. Extracts may be produced by cold extractiontechniques using a variety of different extraction solvents includingwater, fatty solvents (such as olive oil), and alcoholic solvents (e.g.70% ethanol). Cold extraction techniques are typically applied to softerparts of the plant such as leaves and flowers, or in cases wherein thedesired active components of the plant are heat labile. Alternatively,the aforementioned solvents may be used to produce extracts of thedesired plants by a hot extraction technique, wherein said solvents areheated to a high temperature, the precise value of said temperaturebeing dependent on the properties of the chosen solvent, and maintainedat that temperature throughout the extraction process. Hot extractiontechniques are more commonly applied to the harder, tougher parts of theplant, such as bark, woody branches and larger roots. In some cases,sequential extractions can be performed in more than one solvent, and atdifferent temperatures. The plant extract may be used in a concentratedform. Alternatively, the extract may be diluted as appropriate to itsintended use.

WO2004/026857 provides a method for preparing a purified cannabisextract, wherein the cannabinoids are purified to at least 99% wt % THC(Δ9-tetrahydrocannabinol). In this method a crude ethanolic extract ofCannabis plant material is passed through a column of activated charcoaland evaporated by means of rotary evaporation. The resulting THCenriched extract is subsequently passed through a column packed withSephadex LH20 and eluted with chloroform/dichloromethane. The solventused is removed by means of rotary evaporation. In order to furtherincrease the purity of the THC enriched extract, the extract isdissolved in methanol and subsequently in pentane and subjected torotary evaporation twice.

US2015/0126754 describes a) providing a crude solvent extract ofCannabis plant material; b) subjecting the crude extract to thin filmevaporation to obtain a refined extract; c) chromatographicallyfractionating the refined extract to produce one or more high purityfractions having a THC content higher than a preset value and one ormore low purity fractions having a THC content lower than the presetvalue, wherein the preset value is in the range of 95-99% by weight ofdry matter; d) subjecting the one or more high purity fractions toanother thin film evaporation; and e) collecting a THC isolatecontaining at least 97% THC by weight of dry matter; and wherein in stepb) and/or in step d) the thin film evaporation is carried out by usingwiped film evaporation. This method offers the advantage that it yieldsa high purity THC extract in good yield and without using solvents thatpose a health risk. The method further offers the advantage that it ishighly reproducible in that it produces THC-isolate with a specificcannabinoid profile. More particularly, the method yields a THC isolatethat contains at least 97.0-99.5% THC and 0.4-2.0% of othercannabinoids, including at least 0.3% Cannabinol and Cannabidiol (allpercentages by weight of dry matter).

Additional procedures for producing plant extracts (including hotextraction, cold extraction and other techniques) are described inpublications including “Medicinal plants: a field guide to the medicinalplants of the Land of Israel (in Hebrew), author: N. Krispil, Har Gilo,Israel, 1986” and “Making plant medicine, author: R. Cech, pub. byHorizon Herbs, 2000”.

In particular embodiments, plant components of plant-based compositions(e.g., plant extracts) may be sterilized, for example by autoclaving,and then allowed to cool and stored at an appropriate temperature (e.g.,−20° C.). In particular embodiments, further purification to a molecularweight cut-off (e.g., below 10,000 Da) can be carried out, for example,by membrane ultrafiltration before storage.

In particular embodiments, plant-based compositions include carrierssuch as modified amino acids, a surfactant, a detergent, an azone, apyrrolidone, a glycol, or a bile salt. An amino acid is any carboxylicacid having at least one free amine group and includes naturallyoccurring, non-naturally occurring and synthetic amino acids. Poly aminoacids are either peptides or two or more amino acids linked by a bondformed by other groups which can be linked, e.g. an ester, anhydride, oran anhydride linkage. Peptides are two or more amino acids joined by apeptide bond. Peptides can vary in length from dipeptides with two aminoacids to poly peptides with several hundred amino acids. See ChambersBiological Dictionary, editor Peter M. B. Walker, Cambridge, England:Chambers Cambridge, 1989, page 215. Di-peptides, tri-peptides,tetra-peptides, and penta-peptides can also be used.

Carriers which are modified amino acids include acylated fatty acidamino acids (FA-aa) or a salt thereof, which are typically prepared bymodifying the amino acid or an ester thereof by acylation orsulfonation. Acylated fatty acid amino acids include N-acylated FA-aa oran amino acid acylated at its alpha amino group with a fatty acid.

Exemplary N-acylated fatty amino acid salts include sodiumN-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC). Other names for SNACinclude Sodium-N-salicyloyl-8-aminocaprylate, Monosodium8-(N-salicyloylamino) octanoate, N-(salicyloyl)-8-aminooctanoic acidmonosodium salt, monosodium N-{8-(2-hydroxybenzoyl)amino}octanoate, orsodium 8-[(2-hydroxybenzoyl)amino]octanoate. SNAC has the structure:

Salts of SNAC may also be used as a carrier.

Other forms of SNAC include:

wherein X and Z are independently H, a monovalent cation, a divalentmetal cation, or an organic cation. Examples of monovalent cationsinclude sodium and potassium. Examples of divalent cations includecalcium and magnesium. Examples of organic cations include ammonium andtetramethylammonium.

Exemplary modified amino acids, such as N-acylated FA-aas, are providedas compounds I-XXXV (see FIG. 3). Salts of these compounds and otherN-acylated FA-aa can also be used as carriers.

Many of the compounds can be readily prepared from amino acids bymethods within the skill of those in the art based upon the presentdisclosure. For example, compounds I-VII are derived from aminobutyricacid. Compounds VIII-X and XXXI-XXIIV are derived from aminocaproicacid. Compounds XI-XXVI and XXXV are derived from aminocaprylic acid.For example, the modified amino acid compounds above may be prepared byreacting the single amino acid with the appropriate modifying agentwhich reacts with free amino moiety present in the amino acids to formamides. Protecting groups may be used to avoid unwanted side reactionsas would be known to those skilled in the art.

The amino acid can be dissolved in aqueous alkaline solution of a metalhydroxide, e.g., sodium or potassium hydroxide, and heated at atemperature ranging between 5° C. and 70° C., preferably between 10° C.and 40° C., for a period ranging between 1 hour and 4 hours, preferably2.5 hours. The amount of alkali employed per equivalent of NH₂ groups inthe amino acid generally ranges between 1.25 and 3 mmole, preferablybetween 1.5 and 2.25 mmole per equivalent of NH₂. The pH of the solutiongenerally ranges between 8 and 13, preferably ranging between 10 and 12.

Thereafter, the appropriate amino acid modifying agent is added to theamino add solution while stirring. The temperature of the mixture ismaintained at a temperature generally ranging between 5° C. and 70° C.,preferably between 10° C. and 40° C., for a period ranging between 1 and4 hours. The amount of amino acid modifying agent employed in relationto the quantity of amino add is based on the moles of total free NH₂ inthe amino acid. In general, the amino acid modifying agent is employedin an amount ranging between 0.5 and 2.5 mole equivalents, preferablybetween 0.75 and 1.25 equivalents, per molar equivalent of total NH₂group in the amino acid.

The reaction is quenched by adjusting the pH of the mixture with asuitable acid, e.g., concentrated hydrochloric acid, until the pHreaches between 2 and 3. The mixture separates on standing at roomtemperature to form a transparent upper layer and a white or off-whiteprecipitate. The upper layer is discarded, and the modified amino acidis collected from the lower layer by filtration or decantation. Thecrude modified amino acid is then dissolved in water at a pH rangingbetween 9 and 13, preferably between 11 and 13. Insoluble materials areremoved by filtration and the filtrate is dried in vacuo. The yield ofmodified amino acid generally ranges between 30 and 60%, and usually45%.

If desired, amino acid esters, such as, for example benzyl, methyl, orethyl esters of amino acid compounds, may be used to prepare themodified amino acids. The amino acid ester, dissolved in a suitableorganic solvent such as dimethylformamide, pyridine, or tetrahydrofurancan be reacted with the appropriate amino acid modifying agent at atemperature ranging between 5° C. and 70° C., preferably 25° C., for aperiod ranging between 7 and 24 hours. The amount of amino acidmodifying agent used relative to the amino acid ester is the same asdescribed above for amino acids. This reaction may be carried out withor without a base such as, for example, triethylamine ordiisopropylethylamine.

Thereafter, the reaction solvent is removed under negative pressure andthe ester functionality is removed by hydrolyzing the modified aminoacid ester with a suitable alkaline solution, e.g. 1N sodium hydroxide,at a temperature ranging between 50° C. and 80° C., preferably 70° C.,for a period of time sufficient to hydrolyze off the ester group andform the modified amino acid having a free carboxyl group. Thehydrolysis mixture is then cooled to room temperature and acidified,e.g. aqueous 25% hydrochloric acid solution, to a pH ranging between 2and 2.5. The modified amino acid precipitates out of solution and isrecovered by conventional means such as filtration or decantation.Benzyl esters may be removed by hydrogenation in an organic solventusing a transition metal catalyst.

The modified amino acid may be purified by recrystallization or byfractionation on solid column supports. Suitable recrystallizationsolvent systems include acetonitrile, methanol and tetrahydrofuran.Fractionation may be performed on a suitable solid column supports suchas alumina, using methanol/n-propanol mixtures as the mobile phase;reverse phase column supports using trifluoroacetic acid/acetonitrilemixtures as the mobile phase; and ion exchange chromatography usingwater as the mobile phase. When anion exchange chromatography isperformed, preferably a subsequent 0-500 mM sodium chloride gradient isemployed.

In particular embodiments, modified amino acids having the formula

wherein Y is

or SO₂;

R¹ is C₃-C₂₄ alkylene, C₂-C₂₀ alkenylene, C₂-C₂₀ alkynylene,cycloalkylene, or an aromatic, such as arylene;R² is hydrogen, C₁-C₄ alkyl, or C₂-C₄ alkenyl; andR³ is C₁-C₇ alkyl, C₃-C₁₀ cycloalkyl, aryl, thienyl, pyrrolo, orpyridyl, andR³ is optionally substituted by one or more C₁-C₅ alkyl group, C₂-C₄alkenyl group, F, Cl, OH, OR¹, SO₂, COOH, COOR¹ or, SO₃H;may be prepared byreacting in water and the presence of a base a lactam having the formula

with a compound having the formula R³—Y—X, wherein Y, R¹, R², and R³ areas above and X is a leaving group. A lactam as shown in the aboveformula can be prepared, for example by the method described in Olah etal., Synthesis, 537-538 (1979).

In particular embodiments, modified amino acids also include an aminoacid acylated at its alpha amino group with a fatty acid, which can berepresented by the general formula A-X, wherein A is the alpha-aminoacid residue and X is a fatty acid attached by acylation to A'salpha-amino group. The amino acids include cationic and non-cationicamino acids. In particular embodiments the term “non-cationic aminoacid” refers to an amino acid selected from the group consisting ofnon-polar hydrophobic amino acids, polar non-charged amino acids, andpolar acidic amino acids. In particular embodiments the term“non-cationic amino acid” as used herein refers to amino acids selectedfrom the group consisting of Alanine (Ala), Valine (Val), Leucine (Leu),Isoleucine (Ile), Phenylalanine (Phe), Tryptophane (Trp), Methionine(Met), Proline (Pro), Sarcosine, Glycine (Gly), Serine (Ser), Threonine(Thr), Cysteine (Cys), Tyrosine (Tyr), Asparagine (Asn), and Glutamine(Gln), Aspartic acid (Asp), and Glutamic acid

In particular embodiments, the acylated FA-aa includes an alpha aminoacid residue of a non-polar hydrophobic amino acid. In particularembodiments, the acylated FA-aa may be represented by the generalformula A-X, wherein A is the amino acid residue of a non-polarhydrophobic amino acid and X is a fatty acid attached by acylation toA's alpha-amino group. In particular embodiments the term “non-polarhydrophobic amino acid” as used herein refers to categorisation of aminoacids used by the person skilled in the art. In particular embodimentsthe term “non-polar hydrophobic amino acid” refers to an amino acidselected from the group consisting of Alanine (Ala), Valine (Val),Leucine (Leu), Isoleucine (Ile), Phenylalanine (Phe), Tryptophane (Trp),Methionine (Met), Proline (Pro) and Sarcosine.

In particular embodiments, the acylated FA-aa includes the amino acidresidue of a polar non-charged amino acid. In particular embodiments theacylated FA-aa may be represented by the general formula A-X, wherein Ais the amino acid residue of a polar non-charged amino acid and X is afatty acid attached by acylation to A's alpha-amino group. In particularembodiments the term “polar non-charged amino acid” as used hereinrefers to categorisation of amino acids used by the person skilled inthe art. In particular embodiments the term “polar non-charged aminoacid” refers to an amino acid selected from the group consisting ofGlycine (Gly), Serine (Ser), Threonine (Thr), Cysteine (Cys), Tyrosine(Tyr), Asparagine (Asn), and Glutamine (Gln).

In particular embodiments, the acylated FA-aa includes the amino acidresidue of a polar acidic amino acid. In particular embodiments, theacylated FA-aa may be represented by the general formula A-X, wherein Ais the amino acid residue of a polar acidic amino acid and X is a fattyacid attached by acylation to A's alpha-amino group. In particularembodiments, the term “polar acidic amino acid” as used herein refers tocategorisation of amino acids used by the person skilled in the art. Inparticular embodiments, the term “polar acidic amino acid” refers to anamino acid selected from the group consisting of Aspartic acid (Asp) andGlutamic acid (Glu).

In particular embodiments, the amino acid residue of the acylated FA-aaincludes the amino acid residue of an amino acid that is not encoded bythe genetic code. Modifications of amino acids by acylation may bereadily performed using acylation agents known in the art that reactwith the free alpha-amino group of the amino acid.

In particular embodiments, the alpha-amino acids or the alpha-amino acidresidues herein are in the L-form unless otherwise stated.

In particular embodiments, the amino acid residue is in the free acidform and/or a salt thereof, such as a sodium (Na+) salt thereof.

Exemplary embodiments of acylated FA-aas may be represented by thegeneral Fa-aa formula I:

wherein R1 is an alkyl or aryl group including 5 to 19 carbon atoms; R2is H (i.e. hydrogen), CH₃ (i.e. methyl group), or covalently attached toR4 via a (CH₂)₃ group; R3 is H or absent; and R4 is an amino acid sidechain or covalently attached to R2 via a (CH₂)₃ group; or a saltthereof.

The FA-aa can be acylated with a fatty acid including a substituted orunsubstituted alkyl group consisting of 5 to 19 carbon atoms. Inparticular embodiments, the alkyl group consists of 5 to 17 carbonatoms. In particular embodiments, the alkyl group consists of 5-15carbon atoms. In particular embodiments the alkyl group consists of 5-13carbon atoms. In particular embodiments the alkyl group consists of 6carbon atoms.

In particular embodiments, the acylated FA-aa is soluble at intestinalpH values, particularly in the range pH 5.5 to 8.0, such as in the rangepH 6.5 to 7.0. In particular embodiments, the acylated FA-aa is solublebelow pH 9.0.

In particular embodiments, the acylated FA-aa has a solubility of atleast 5 mg/mL. In particular embodiments, the acylated FA-aa has asolubility of at least 10 mg/mL. In particular embodiments, the acylatedFA-aa has a solubility of at least 20 mg/mL. In particular embodiments,the acylated FA-aa has a solubility of at least 30 mg/mL. In particularembodiments, the acylated FA-aa has a solubility of at least 40 mg/mL.In particular embodiments, the acylated FA-aa has a solubility of atleast 50 mg/mL. In particular embodiments, the acylated FA-aa has asolubility of at least 60 mg/mL. In particular embodiments, the acylatedFA-aa has a solubility of at least 70 mg/mL. In particular embodiments,the acylated FA-aa has a solubility of at least 80 mg/mL. In particularembodiments, the acylated FA-aa has a solubility of at least 90 mg/mL.In particular embodiments, the acylated FA-aa has a solubility of atleast 100 mg/mL. In particular embodiments, solubility of the acylatedFA-aa is determined in an aqueous solution at a pH value 1 unit above orbelow pKa of the FA-aa at 37° C. In particular embodiments, solubilityof the acylated FA-aa is determined in an aqueous solution at pH 8 at37° C. In particular embodiments, solubility of the acylated FA-aa isdetermined in an aqueous solution at a pH value 1 unit above or below plof the FA-aa at 37° C. In particular embodiments, solubility of theacylated FA-aa is determined in an aqueous solution at a pH value 1units above or below pl of the FA-aa at 37° C., wherein said FA-aa twoor more ionisable groups with opposite charges. In particularembodiments, solubility of the FA-aa is determined in an aqueous 50 mMsodium phosphate buffer, pH 8.0 at 37° C.

In particular embodiments the acylated FA-aa is selected from the groupconsisting of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j),(k), (l), (m), (n), (o), (p), (q), and (r), wherein R1 is an alkyl groupincluding 5 to 19 carbon atoms, R2 is H (i.e. hydrogen) or CH₃ (i.e.methyl group), and R3 is H; or a salt or the free acid form thereof.Formulas (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l),(m), (n), (o), (p), (q), and (r) are provided in FIG. 4.

In particular embodiments, the acylated FA-aa can be selected from oneor more of sodium N-dodecanoyl alaninate, N-dodecanoyl-L-alanine, sodiumN-dodecanoyl isoleucinate, N-dodecanoyl-L-isoleucine, sodiumN-dodecanoyl leucinate, N-dodecanoyl-L-leucine, sodium N-dodecanoylmethioninate, N-dodecanoyl-L-methionine, sodium N-dodecanoylphenylalaninate, N-dodecanoyl-L-phenylalanine, sodium N-dodecanoylprolinate, N-dodecanoyl-L-proline, sodium N-dodecanoyl tryptophanate,N-dodecanoyl-L-tryptophane, sodium N-dodecanoyl valinate,N-dodecanoyl-L-valine, sodium N-dodecanoyl sarcosinate,N-dodecanoyl-L-sarcosine, sodium N-oleoyl sarcosinate, sodium N-decylleucine, sodium N-decanoyl alaninate, N-decanoyl-L-alanine, sodiumN-decanoyl leucinate, N-decanoyl-L-leucine, sodium N-decanoylphenylalaninate, N-decanoyl-L-phenylalanine, sodium N-decanoyl valinate,N-decanoyl-L-valine, sodium N-decanoyl isoleucinate,N-decanoyl-L-isoleucine, sodium N-decanoyl methioninate,N-decanoyl-L-methionine, sodium N-decanoyl prolinate,N-decanoyl-L-proline, sodium N-decanoyl threoninate,N-decanoyl-L-threonine, sodium N-decanoyl tryptophanate,N-decanoyl-L-tryptophane, sodium N-decanoyl sarcosinate,N-decanoyl-L-Sarcosine, N-dodecanoyl asparaginate,N-dodecanoyl-L-asparagine, sodium N-dodecanoyl aspartic acid,N-dodecanoyl-L-aspartic acid, sodium N-dodecanoyl cysteinate,N-dodecanoyl-L-cysteine, sodium N-dodecanoyl glutaminate,N-dodecanoyl-L-glutamine, sodium N-dodecanoyl glycinate,N-dodecanoyl-L-glycine, sodium N-dodecanoyl serinate,N-dodecanoyl-L-serine, sodium N-dodecanoyl threoninate,N-dodecanoyl-L-threonine, sodium N-dodecanoyl tyrosinate,N-dodecanoyl-L-tyrosine, sodium N-decanoyl asparaginate,N-decanoyl-L-asparagine, sodium N-decanoyl aspartic acid,N-decanoyl-L-aspartic acid, sodium N-decanoyl cysteinate,N-decanoyl-L-cysteine, sodium N-decanoyl glutaminate,N-decanoyl-L-glutamine, sodium N-decanoyl glycinate,N-decanoyl-L-glycine, sodium N-decanoyl serinate, N-decanoyl-L-serine,sodium N-decanoyl tyrosinate, N-decanoyl-L-tyrosine, sodium N-dodecanoylasparaginate, sodium N-dodecanoyl glutamic acid, N-dodecanoyl-L-glutamicacid, sodium N-decanoyl glutamic acid, N-decanoyl-L-glutamic acid,Amisoft HS-11 P (sodium Stearoyl Glutamate, Amisoft MS-11 (sodiumMyristoyl Glutamate), Amisoft LS-11 (sodium Dodecanoyl Glutamate),Amisoft CS-11 (sodium Cocoyl Glutamate), sodium N-cocoyl glutamate,Amisoft HS-11 P, Amisoft HS-11 P (sodium N-stearoyl glutamate), (sodiumN-myristoyl glutamate)), (sodium N-dodecanoyl glutamate), and AmisoftHS-11 P.

The following acylated FA-aas are commercially available:

Provider Brand Name Chemical Name (per Apr. 14, 2011) Hamposyl L-95sodium N-dodecanoyl sarcosinate Chattem Chemicals Hamposyl O sodiumN-oleoyl sarcosinate Chattem Chemicals Hamposyl C sodium N-cocoylsarcosinate Chattem Chemicals Hamposyl L-30 sodium N-dodecanoylsarcosinate Chattem Chemicals Amisoft HS-11 P sodium N-stearoylglutamate Ajinomoto Amisoft LS-11 sodium N-dodecanoyl glutamateAjinomoto Amisoft CS-11 sodium N-cocoyl glutamate Ajinomoto AmisoftMS-11 sodium N-myristoyl glutamate Ajinomoto Amilite GCS-11 sodiumN-cocoyl glycinate Ajinomoto

In particular embodiments the terms “fatty acid N-acylated amino acid”,“fatty acid acylated amino acid”, or “acylated amino acid” are usedinterchangeably herein and refer to an amino acid that is acylated witha fatty acid at its alpha-amino group.

Particular embodiments utilize vegetable matter with low solubility, orvery low solubility. Particular embodiments utilize vegetable matterthat is essentially water insoluble. In particular embodiments,solubility in water is defined as low to zero by the United Statespharmacopeia (USP 32) according to the amount of water necessary for thedissolution of one part of solute: Low solubility: 100 to 1000 parts ofwater necessary for dissolution of one part of solute; very lowsolubility: 1000 to 10 000 parts of water necessary; essentially waterinsoluble more than 10 000 parts of water necessary. At a basic pH,however, SNAC and other modified amino acids and FA-aas described hereinare water soluble. Thus, the administration benefits, as describedherein could not be reasonably predicted. In particular embodiments,very low solubility can refer to a solubility in water or an aqueoussolution of less than 1 mg/ml, less than 0.1 mg/ml, or less than 0.01mg/ml.

In particular embodiments, N-acylated fatty amino acids act asabsorption enhancing agents, thereby creating an administration benefit.Absorption enhancing agents refer to compounds that promotegastrointestinal absorption. Absorption enhancing agents can improvedrug absorption by improving the solubility of the drug in thegastrointestinal tract or by enhancing membrane penetration, as comparedto a formulation that does not include the absorption enhancing agents.Additional examples of absorption enhancing agents include surfactants,detergents, azones, pyrrolidones, glycols or bile salts.

In particular embodiments, N-acylated fatty amino acids act asbioavailability enhancing agents. Bioavailability refers to the fractionof active ingredient that is actually absorbed by a subject and reachesthe bloodstream. In particular embodiments, bioavailability enhancingagents increase the fraction of active ingredient in the bloodstream orresult in detection of active ingredient in the bloodstream earlier intime, as compared to a formulation that does not include thebioavailability enhancing agent.

In particular embodiments, additional administration benefits created byabsorption enhancing agents and/or bioavailability enhancing agentsinclude faster onset of action, higher peak concentrations, faster timeto peak concentrations, shorter duration of action, increased subjectivetherapeutic efficacy, and/or increased objective therapeutic efficacy ascompared to a control plant-based composition or oral formulation basedon the same, similar in all aspects but for inclusion of the absorptionenhancing agents and/or bioavailability enhancing agents.

Embodiments utilizing absorption enhancing agents and/or bioavailabilityenhancing agents (e.g., and in particular embodiments, N-acylated fattyamino acids) can be beneficial because many oral plant-basedcompositions designed to address various physiological conditions areinadequate because they are characterized by a delayed onset of action,and low bioavailability. Delayed onset of action presents challenges inclinical indications that require rapid therapeutic effect (e.g. painand migraine); and low bioavailability requires patients to ingestsignificantly higher doses than would be required by alternative dosingforms (e.g. smoking, vaping). Particular embodiments disclosed hereinprovide plant-based composition oral formulations with improvedbioavailability and shorter time to onset of therapeutic effect.

As stated, in particular embodiments, N-acylated fatty amino acids actas subjective therapy enhancing agents. Subjective therapy enhancementrefers to a noticeable alleviation of a symptom, as perceived by asubject. In particular embodiments, subjective therapy enhancing agentsincrease the alleviation of a symptom or alleviate a symptom morequickly, as compared to a formulation that does not include thesubjective therapy enhancing agent.

In particular embodiments, N-acylated fatty amino acids act as objectivetherapy enhancing agents. Objective therapy enhancement refers toalleviation of a clinical measure, such as a nutritional deficiencydetected by a blood or saliva assay or a test of wellness, asadministered by a physician. In particular embodiments, objectivetherapy enhancing agents increase the alleviation of an objectiveclinical measure or result in alleviation more quickly, as compared to aformulation that does not include the objective therapy enhancing agent.

Particular embodiments include cannabis and an absorption enhancingagent and/or bioavailability enhancing agent. These embodiments canallow more rapid cannabis absorption and higher bioavailability comparedto cannabis ingested by currently available oral dosage forms.

In particular embodiments, carriers disclosed herein createadministration benefits selected from: increased absorption, increasedbioavailability, faster onset of action, higher peak concentrations,faster time to peak concentrations, shorter duration of action,increased subjective therapeutic efficacy, increased objectivetherapeutic efficacy, improved taste, and improved mouthfeel.Administration benefits related to increased absorption, increasedbioavailability, faster onset of action, higher peak concentrations,faster time to peak concentrations, shorter duration of action canalleviate adverse conditions more rapidly (for example, alleviation ofpain). “Mouthfeel” refers to non-taste-related aspects of thepleasantness experienced by a person while ingesting (e.g., chewing orswallowing) an oral dosage form. Aspects of mouthfeel include thehardness and brittleness of a composition, whether the composition ischewy, gritty, oily, creamy, watery, sticky, easily dissolved,astringent, effervescent, and the like, and the size, shape, and form ofthe composition (tablet, powder, gel, etc.).

Plant-based compositions can be manufactured for administration to asubject by adding vegetable matter, a carrier that provides anadministration benefit, and one or more excipients, mixing, suspending,dissolving, blending, granulating, tableting, encapsulating, orperforming other dosage-form-specific procedures, followed by packaging.For clarity, carriers contribute to providing an administration benefit.Excipients can, but need not, contribute to an administration benefit.

Particular embodiments include plant-based compositions prepared as oralformulations. Exemplary oral formulations include capsules, coatedtablets, edibles, elixirs, emulsions, gels, gelcaps, granules, gums,juices, liquids, oils, pastes, pellets, pills, powders,rapidly-dissolving tablets, sachets, semi-solids, sprays, solutions,suspensions, syrups, tablets, etc.

Exemplary excipient classes include binders, buffers, chelators, coatingagents, colorants, complexation agents, diluents (i.e., fillers),disintegrants, emulsifiers, flavoring agents, glidants, lubricants,preservatives, releasing agents, surfactants, stabilizing agents,solubilizing agents, sweeteners, thickening agents, wetting agents, andvehicles.

Binders are substances used to cause adhesion of powder particles ingranulations. Exemplary binders include acacia, compressible sugar,gelatin, sucrose and its derivatives, maltodextrin, cellulosic polymers,such as ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium and methylcellulose, acrylicpolymers, such as insoluble acrylate ammoniomethacrylate copolymer,polyacrylate or polymethacrylic copolymer, povidones, copovidones,polyvinylalcohols, alginic acid, sodium alginate, starch, pregelatinizedstarch, guar gum, and polyethylene glycol.

Colorants may be included in the oral formulations to impart color tothe formulation. Exemplary colorants include grape skin extract, beetred powder, beta carotene, annato, carmine, turmeric, and paprika.Additional colorants include FD&C Red No. 3, FD&C Red No. 20, FD&CYellow No. 6, FD&C Blue No. 2, D&C Green No. 5, FD&C Orange No. 5, D&CRed No. 8, caramel, and ferric oxide.

Diluents can enhance the granulation of oral formulations. Exemplarydiluents include microcrystalline cellulose, sucrose, dicalciumphosphate, starches, lactose and polyols of less than 13 carbon atoms,such as mannitol, xylitol, sorbitol, maltitol and pharmaceuticallyacceptable amino acids, such as glycin.

Disintegrants also may be included in the oral formulations in order tofacilitate dissolution. Disentegrants, including permeabilising andwicking agents, are capable of drawing water or saliva up into the oralformulations which promotes dissolution from the inside as well as theoutside of the oral formulations. Such disintegrants, permeabilisingand/or wicking agents that may be used include starches, such as cornstarch, potato starch, pre-gelatinized and modified starches thereof,cellulosic agents, such as Ac-di-sol, montmorrilonite clays,cross-linked PVP, sweeteners, bentonite, microcrystalline cellulose,croscarmellose sodium, alginates, sodium starch glycolate, gums, such asagar, guar, locust bean, karaya, pectin, Arabic, xanthan and tragacanth,silica with a high affinity for aqueous solvents, such as colloidalsilica, precipitated silica, maltodextrins, beta-cyclodextrins,polymers, such as carbopol, and cellulosic agents, such ashydroxymethylcellulose, hydroxypropylcellulose andhydroxyopropylmethylcellulose. Dissolution of the oral formulations maybe facilitated by including relatively small particles sizes of theingredients used.

Exemplary dispersing or suspending agents include acacia, alginate,dextran, fragacanth, gelatin, hydrogenated edible fats, methylcellulose,polyvinylpyrrolidone, sodium carboxymethyl cellulose, sorbitol syrup,and synthetic natural gums.

Exemplary emulsifiers include acacia and lecithin.

Flavorants are natural or artificial compounds used to impart a pleasantflavor and often odor to oral formulations. Exemplary flavorantsinclude, natural and synthetic flavor oils, flavoring aromatics,extracts from plants, leaves, flowers, and fruits and combinationsthereof. Such flavorants include anise oil, cinnamon oil, vanilla,vanillin, cocoa, chocolate, natural chocolate flavor, menthol, grape,peppermint oil, oil of wintergreen, clove oil, bay oil, anise oil,eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oilof bitter almonds, cassia oil; citrus oils, such as lemon, orange, limeand grapefruit oils; and fruit essences, including apple, pear, peach,berry, wildberry, date, blueberry, kiwi, strawberry, raspberry, cherry,plum, pineapple, and apricot. In particular embodiments, flavorants thatmay be used include natural berry extracts and natural mixed berryflavor, as well as citric and malic acid.

Glidants improve the flow of powder blends during manufacturing andminimize oral formulation weight variation. Exemplary glidants includesilicon dioxide, colloidal or fumed silica, magnesium stearate, calciumstearate, stearic acid, cornstarch, and talc.

Lubricants are substances used in oral formulations that reduce frictionduring composition compression. Exemplary lubricants include stearicacid, calcium stearate, magnesium stearate, zinc stearate, talc, mineraland vegetable oils, benzoic acid, poly(ethylene glycol), glycerylbehenate, stearyl fumarate, and sodium lauryl sulfate.

Exemplary preservatives include methyl p-hydroxybenzoates, propylp-hydroxybenzoates, and sorbic acid.

Exemplary sweeteners include aspartame, dextrose, fructose, highfructose corn syrup, maltodextrin, monoammonium glycyrrhizinate,neohesperidin dihydrochalcone, potassium acesulfame, saccharin sodium,stevia, sucralose, and sucrose.

Particular embodiments include swallowable compositions. Swallowablecompositions are those that do not readily dissolve when placed in themouth and may be swallowed whole without chewing or discomfort. U.S.Pat. Nos. 5,215,754 and 4,374,082 describe methods for preparingswallowable compositions. In particular embodiments, swallowablecompositions may have a shape containing no sharp edges and a smooth,uniform and substantially bubble free outer coating.

To prepare swallowable compositions, each of the ingredients may becombined in intimate admixture with a suitable carrier according toconventional compounding techniques. In particular embodiments of theswallowable compositions, the surface of the compositions may be coatedwith a polymeric film. Such a film coating has several beneficialeffects. First, it reduces the adhesion of the compositions to the innersurface of the mouth, thereby increasing the subject's ability toswallow the compositions. Second, the film may aid in masking theunpleasant taste of certain ingredients. Third, the film coating mayprotect the compositions from atmospheric degradation. Polymeric filmsthat may be used in preparing the swallowable compositions include vinylpolymers such as polyvinylpyrrolidone, polyvinyl alcohol and acetate,cellulosics such as methyl and ethyl cellulose, hydroxyethyl celluloseand hydroxylpropyl methylcellulose, acrylates and methacrylates,copolymers such as the vinyl-maleic acid and styrene-maleic acid types,and natural gums and resins such as zein, gelatin, shellac and acacia.

In particular embodiments, the oral formulations may include chewablecompositions. Chewable compositions are those that have a palatabletaste and mouthfeel, are relatively soft and quickly break into smallerpieces and begin to dissolve after chewing such that they are swallowedsubstantially as a solution.

U.S. Pat. No. 6,495,177 describes methods to prepare chewablecompositions with improved mouthfeel. U.S. Pat. No. 5,965,162, describeskits and methods for preparing comestible units which disintegratequickly in the mouth, especially when chewed.

In order to create chewable compositions, certain ingredients should beincluded to achieve the attributes just described. For example, chewablecompositions should include ingredients that create pleasant flavor andmouthfeel and promote relative softness and dissolvability in the mouth.The following discussion describes ingredients that may help to achievethese characteristics.

Sugars such as white sugar, corn syrup, sorbitol (solution), maltitol(syrup), oligosaccharide, isomaltooligosaccharide, sucrose, fructose,lactose, glucose, lycasin, xylitol, lactitol, erythritol, mannitol,isomaltose, dextrose, polydextrose, dextrin, compressible cellulose,compressible honey, compressible molasses and mixtures thereof may beadded to improve mouthfeel and palatability. Fondant or gums such asgelatin, agar, arabic gum, guar gum, and carrageenan may be added toimprove the chewiness of the compositions. Fatty materials that may beused include vegetable oils (including palm oil, palm hydrogenated oil,corn germ hydrogenated oil, castor hydrogenated oil, cotton-seed oil,olive oil, peanut oil, palm olein oil, and palm stearin oil), animaloils (including refined oil and refined lard whose melting point rangesfrom 30° to 42° C.), Cacao fat, margarine, butter, and shortening.

Alkyl polysiloxanes (commercially available polymers sold in a varietyof molecular weight ranges and with a variety of different substitutionpatterns) also may be used to enhance the texture, the mouthfeel, orboth of chewable compositions. By “enhance the texture” it is meant thatthe alkyl polysiloxane improves one or more of the stiffness, thebrittleness, and the chewiness of the chewable composition, relative tothe same preparation lacking the alkyl polysiloxane. By “enhance themouthfeel” it is meant that the alkyl polysiloxane reduces the grittytexture of the chewable composition once it has liquefied in the mouth,relative to the same preparation lacking the alkyl polysiloxane.

Alkyl polysiloxanes generally include a silicon and oxygen-containingpolymeric backbone with one or more alkyl groups pending from thesilicon atoms of the back bone. Depending upon their grade, they canfurther include silica gel. Alkyl polysiloxanes are generally viscousoils. Exemplary alkyl polysiloxanes that can be used in swallowable,chewable or dissolvable compositions include monoalkyl or dialkylpolysiloxanes, wherein the alkyl group is independently selected at eachoccurrence from a C₁-C₆-alkyl group optionally substituted with a phenylgroup. A specific alkyl polysiloxane that may be used is dimethylpolysiloxane (generally referred to as simethicone). More specifically,a granular simethicone preparation designated simethicone GS may beused. Simethicone GS is a preparation which contains 30% simethiconeUSP.

Simethicone USP contains not less than 90.5% by weight(CH₃)₃—Si{OSi(CH₃)₂}CH₃ in admixture with 4.0% to 7.0% by weight SiO₂.

To prevent the stickiness that can appear in some chewable compositionsand to facilitate conversion of the active ingredients to emulsion orsuspension upon taking, the compositions may further include emulsifierssuch as glycerin fatty acid ester, sorbitan monostearate, sucrose fattyacid ester, lecithin and mixtures thereof. In particular embodiments,one or more of such emulsifiers may be present in an amount of 0.01% to5.0%, by weight of the administered formulations. If the level ofemulsifier is lower or higher, in particular embodiments, anemulsification cannot be realized, or wax value will rise.

Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for reconstitution with water or other suitable vehiclesbefore use.

In addition to those described above, any appropriate fillers andexcipients may be utilized in preparing the swallowable, chewable and/ordissolvable compositions or any other oral formulation described hereinso long as they are consistent with the described objectives.

Oral formulations also include edibles. Edibles refer to any productthat can be consumed as a food or a drink. In some cases, edibles aremade by infusion of plant extracts into a foodstuff. Examples of ediblefoods appropriate for use include candy, a candy bar, bread, a brownie,cake, cheese, chocolate, cocoa, a cookie, gummy candy, a lollipop, amint, a pastry, peanut butter, popcorn, a protein bar, rice cakes,yogurt, etc. While technically not edible, gums can also be used.Examples of edible drinks include beer, juice, flavored milk, flavoredwater, liquor, milk, punch, a shake, soda, tea, and water. In particularembodiments, edibles are made by combining a plant extract withingredients used to make an edible. Examples include butters and oils.Exemplary oils include coconut oil, grape seed oil, olive oil, palm oil,papaya seed oil, peanut oil, sesame oil, sprouted wheat oil, wheat germoil, or any combination thereof.

Oral formulations can be individually wrapped or packaged as multipleunits in one or more packages, cans, vials, blister packs, or bottles ofany size. Doses are sized to provide therapeutically effective amounts.

In particular embodiments, the oral formulations include vegetablematter (e.g., plant parts or extracts) of at least 0.1% w/v or w/w ofthe oral formulation; at least 1% w/v or w/w of oral formulation; atleast 10% w/v or w/w of oral formulation; at least 20% w/v or w/w oforal formulation; at least 30% w/v or w/w of oral formulation; at least40% w/v or w/w of oral formulation; at least 50% w/v or w/w of oralformulation; at least 60% w/v or w/w of oral formulation; at least 70%w/v or w/w of oral formulation; at least 80% w/v or w/w of oralformulation; at least 90% w/v or w/w of oral formulation; at least 95%w/v or w/w of oral formulation; or at least 99% w/v or w/w of oralformulation.

In particular embodiments, the oral formulations include carrier of atleast 0.1% w/v or w/w of the oral formulation; at least 1% w/v or w/w oforal formulation; at least 10% w/v or w/w of oral formulation; at least20% w/v or w/w of oral formulation; at least 30% w/v or w/w of oralformulation; at least 40% w/v or w/w of oral formulation; at least 50%w/v or w/w of oral formulation; at least 60% w/v or w/w of oralformulation; at least 70% w/v or w/w of oral formulation; at least 80%w/v or w/w of oral formulation; at least 90% w/v or w/w of oralformulation; at least 95% w/v or w/w of oral formulation; or at least99% w/v or w/w of oral formulation.

In particular embodiments, the oral formulations include excipient of atleast 0.1% w/v or w/w of the oral formulation; at least 1% w/v or w/w oforal formulation; at least 10% w/v or w/w of oral formulation; at least20% w/v or w/w of oral formulation; at least 30% w/v or w/w of oralformulation; at least 40% w/v or w/w of oral formulation; at least 50%w/v or w/w of oral formulation; at least 60% w/v or w/w of oralformulation; at least 70% w/v or w/w of oral formulation; at least 80%w/v or w/w of oral formulation; at least 90% w/v or w/w of oralformulation; at least 95% w/v or w/w of oral formulation; or at least99% w/v or w/w of oral formulation.

In particular embodiments, 10 g of dried plant extract may be used in150 ml of water. This may give an effective concentration of between 1and 99% (w/w) plant extract, between 2 and 80% (w/w) plant extract, andbetween 5 and 50% (w/w) plant extract.

Excipients are commercially available from companies such as AldrichChemical Co., FMC Corp, Bayer, BASF, Alexi Fres, Witco, Mallinckrodt,Rhodia, ISP, and others.

Additional information can be found in WADE & WALLER, HANDBOOK OFPHARMACEUTICAL EXCIPIENTS (2nd ed. 1994) and Remington's PharmaceuticalSciences, 18th Ed. Mack Printing Company, 1990. Moreover, formulationscan be prepared to meet sterility, pyrogenicity, general safety, andpurity standards as required by U.S. FDA and/or other relevant foreignregulatory agencies.

Plant-based compositions disclosed herein can be used to treat subjects(humans, veterinary animals (dogs, cats, reptiles, birds, etc.),livestock (horses, cattle, goats, pigs, chickens, etc.), and researchanimals (monkeys, rats, mice, fish, etc.)). Treating subjects includesproviding therapeutically effective amounts. Therapeutically effectiveamounts include those that provide effective amounts, prophylactictreatments, and/or therapeutic treatments.

An “effective amount” is the amount of a plant-based compositionnecessary to result in a desired physiological change in a subject.Effective amounts are often administered for research purposes.Representative effective amounts disclosed herein can reduce painperception in an animal model (neuropathic pain, acute pain, visceralpain), stimulate appetite in an animal model, reduce seizures (e.g.,epileptic seizures) in an animal model, reverse bone loss in an animalmodel, relieve migraine (vasoconstrict cranial blood vessels) in ananimal model, treat addiction in an animal model, reduce anxiety in ananimal model, and/or reduce symptoms of asthma in an animal model.

A “prophylactic treatment” includes a treatment administered to asubject who does not display signs or symptoms of a disease ornutritional deficiency, or displays only early signs or symptoms of adisease or nutritional deficiency, such that treatment is administeredfor the purpose of diminishing, preventing, or decreasing the risk ofdeveloping the disease or nutritional deficiency further. Thus, aprophylactic treatment functions as a preventative treatment against thedevelopment of diseases or nutritional deficiencies.

As one example of a prophylactic treatment, an oral formulationdisclosed herein can be administered to a subject who is at risk ofdeveloping a migraine headache. An effective prophylactic treatment of amigraine headache occurs when the number of migraines per monthexperienced by a subject is reduced by at least 10% or in particularembodiments, by 25%.

As another example of a prophylactic treatment, an oral formulationdisclosed herein can be administered to a subject who is at risk ofhaving an epileptic seizure. An effective prophylactic treatment ofepileptic seizures occurs when the number of seizures per month isreduced by at least 10% or in particular embodiments, by 25%.

As another example of a prophylactic treatment, an oral formulationdisclosed herein can be administered to a subject who is at risk ofsuffering from neuropathic pain. An effective prophylactic treatment ofneuropathic pain occurs when the occurrence of the neuropathic pain isreduced by at least 10%, or in particular embodiments, by 25% asmeasured by a standard subjective or objective pain assessment.

As another example of a prophylactic treatment, an oral formulationdisclosed herein can be administered to a subject who is at risk ofdeveloping breakthrough pain. An effective prophylactic treatment ofbreakthrough pain occurs when the occurrence of breakthrough pain isreduced by 10%, and in particular embodiments, by 25% by a standardsubjective or objective pain assessment.

As another example of a prophylactic treatment, an oral formulationdisclosed herein can be administered to a subject who is at risk ofdeveloping chemotherapy induced nausea and vomiting (CINV). An effectiveprophylactic treatment of CINV occurs when CINV is reduced by 10%, andin particular embodiments, by 25% measured by a standard subjective orobjective CINV assessment.

As an example of a prophylactic treatment of a nutritional deficiency,an oral formulation disclosed herein can be administered to a subjectwho is at risk of developing rickets from insufficient vitamin C, anemiafrom insufficient dietary iron, and/or bone loss from insufficientcalcium. An effective prophylactic treatment of these conditions occurswhen the conditions are avoided or delayed due to nutritionalsupplementation with an oral formulation disclosed herein.

A “therapeutic treatment” includes a treatment administered to a subjectwho has a disease or nutritional deficiency and is administered to thesubject for the purpose of curing or reducing the severity of thedisease or nutritional deficiency.

As one example of a therapeutic treatment, an oral formulation disclosedherein can be administered to a subject who has a migraine headache. Aneffective therapeutic treatment of the migraine headache occurs when theseverity of the headache is reduced or relieved completely and/or theheadache resolves more quickly measured by a standard subjective orobjective headache assessment.

Another example of a therapeutic treatment includes administration of anoral formulation disclosed herein to a subject experiencing CINV. Atherapeutic treatment of CINV occurs when the vomiting is reduced orceases (or ceases more quickly) and the nausea is relieved measured by astandard subjective or objective CINV assessment.

Another example of a therapeutic treatment, includes administration ofan oral formulation disclosed to a subject who has osteoporosis. Aneffective therapeutic treatment of osteoporosis occurs when bone densityhas increased by 10% and in particular embodiments, by 25%.

Another example of a therapeutic treatment includes administration of anoral formulation disclosed herein to a subject who has anxiety. Aneffective therapeutic treatment of anxiety occurs when the severity ofthe anxiety is reduced or relieved completely and/or more quicklymeasured by a standard subjective or objective anxiety assessment.

Another example of a therapeutic treatment includes administration of anoral formulation disclosed herein to a subject who has multiplesclerosis. An effective therapeutic treatment of multiple sclerosisoccurs when the score in a standard walk test improves by 10% and inparticular embodiments, by 25%.

As one example of a therapeutic treatment of a nutritional deficiency,an oral formulation disclosed herein can be administered to a subjectwho has rickets from insufficient vitamin C, anemia from insufficientdietary iron, and/or bone loss from insufficient calcium. An effectivetherapeutic treatment of these conditions occurs when the conditions arereduced or resolved due to nutritional supplementation with an oralformulation disclosed herein.

Therapeutic treatments can be distinguished from effective amounts basedon the presence or absence of a research component to theadministration. As will be understood by one of ordinary skill in theart, however, in human clinical trials effective amounts, prophylactictreatments and therapeutic treatments can overlap.

For administration, therapeutically effective amounts (also referred toherein as doses) can be initially estimated based on results from invitro assays and/or animal model studies. Such information can be usedto more accurately determine useful doses in subjects of interest.

The actual dose amount administered to a particular subject can bedetermined by the subject, a physician, veterinarian, or researchertaking into account parameters such as physical, physiological andpsychological factors including target, body weight, condition, previousor concurrent therapeutic interventions, and/or idiopathy of thesubject.

Useful doses can range from 0.1 to 5 μg/kg or from 0.5 to 1 μg/kg. Inother non-limiting examples, a dose can include 1 μg/kg, 5 μg/kg, 10μg/kg, 15 μg/kg, 20 μg/kg, 25 μg/kg, 30 μg/kg, 35 μg/kg, 40 μg/kg, 45μg/kg, 50 μg/kg, 55 μg/kg, 60 μg/kg, 65 μg/kg, 70 μg/kg, 75 μg/kg, 80μg/kg, 85 μg/kg, 90 μg/kg, 95 μg/kg, 100 μg/kg, 150 μg/kg, 200 μg/kg,250 μg/kg, 350 μg/kg, 400 μg/kg, 450 μg/kg, 500 μg/kg, 550 μg/kg, 600μg/kg, 650 μg/kg, 700 μg/kg, 750 μg/kg, 800 μg/kg, 850 μg/kg, 900 μg/kg,950 μg/kg, 1000 μg/kg, 0.1 to 5 mg/kg or from 0.5 to 1 mg/kg. In othernon-limiting examples, a dose can include 1 mg/kg, 5 mg/kg, 10 mg/kg, 15mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg,350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 550 mg/kg, 600 mg/kg, 650mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg, 950 mg/kg,1000 mg/kg or more.

Therapeutically effective amounts can be achieved by administeringsingle or multiple doses during the course of a treatment regimen (e.g.,hourly, every 2 hours, every 3 hours, every 4 hours, every 6 hours,every 9 hours, every 12 hours, every 18 hours, daily, every other day,every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2weeks, every 3 weeks, or monthly).

One or more active agent(s) can be administered simultaneously or withina selected time window, such as within 10 minutes, 1 hour, 3 hour, 10hour, 15 hour, 24 hour, or 48 hour time windows or when thecomplementary active agent(s) is within a clinically-relevanttherapeutic window.

The Exemplary Embodiments and Examples below are included to demonstrateparticular embodiments of the disclosure. Those of ordinary skill in theart should recognize in light of the present disclosure that manychanges can be made to the specific embodiments disclosed herein andstill obtain a like or similar result without departing from the spiritand scope of the disclosure.

EXEMPLARY EMBODIMENTS

-   1. A plant-based composition including vegetable matter and an    N-acylated fatty amino acid or a salt thereof.-   2. A plant-based composition of embodiment 1 including a botanical    product.-   3. A plant-based composition of embodiment 1 or 2 wherein the    vegetable matter is derived from Calophyllum brasiliense,    Calophyllum caledonicum, Calophyllum inophyllum, Calophyllum    soulattri, Uncaria tomentosa, Thymus vulgaris, Matricaria recutita,    Salix alba, Calendula officinalis, Usnea barbata, Ligusticum    porterii-osha, Gaultheria procumbens, Camellia sinensis, Vaccinium    myrtillus, Melissa officinalis, Allium sativum, Camellia sinensis,    Krameria triandra, Punica granatum, Viburnum plicatum, Nicotiana    tabacum, Duboisia hopwoodii, Asclepias syriaca, Curcuma longa,    Cannabis sativa, Cannabis indica, Cannabis ruderalis and/or Acer    spp, or an extract thereof.-   4. A plant-based composition of any of embodiments 1-3 wherein the    vegetable matter is derived from cannabis.-   5. A plant-based composition of any of embodiments 1-4 wherein the    vegetable matter is derived from Cannabis sativa, Cannabis    ruderalis, or Cannabis indica.-   6. A plant-based composition of any of embodiments 1-5 including a    cannabis extract.-   7. A plant-based composition of any of embodiments 1-6 including    cannabinoids.-   8. A plant-based composition of any of embodiments 1-7 including    Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD), cannabigerol    (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol    (CBDL), cannabicyclol (CBL), cannabivarin (CBV),    tetrahydrocannabivarin (THCV), cannabidivarin (CBDV),    cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol    monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid    (CBDA), Cannabinol propyl variant (CBNV), cannabitriol (CBO),    tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarinic acid    (THCVA), and/or mixtures thereof.-   9. A plant-based composition of any of embodiments 1-8 including    flavonoid compounds, terpenes, or terpenoids.-   10. A plant-based composition of any of embodiments 1-9 wherein the    N-acylated fatty amino acid includes one or more of Compounds I-XXXV    (FIG. 3), or Compounds a-r (FIG. 4).-   11. A plant-based composition of any of embodiments 1-10 wherein the    N-acylated fatty amino acid includes    monosodium-N-salicyloyl-8-aminocaprylate,    disodium-N-salicyloyl-8-aminocaprylate, and    N-(salicyloyl)-8-aminocaprylic acid.-   12. A plant-based composition of any of embodiments 1-11 wherein the    N-acylated fatty amino acid or a salt thereof includes

-    wherein X and Z are independently H, a monovalent cation, a    divalent metal cation, or an organic cation.-   13. A plant-based composition of embodiment 12, wherein the    monovalent cation includes sodium or potassium.-   14. A plant-based composition of embodiment 12, wherein the metal    cation includes calcium or magnesium.-   15. A plant-based composition of embodiment 12, wherein the organic    cation includes ammonium or tetramethylammonium.-   16. The plant-based composition of embodiment 12, wherein X is H.-   17. The plant-based composition of embodiment 12, wherein X is a    monovalent cation including sodium or potassium.-   18. The plant-based composition of embodiment 12, wherein X is a    divalent metal cation including calcium or magnesium.-   19. The plant-based composition of embodiment 12, wherein X is an    organic cation including ammonium or tetramethylammonium.-   20. The plant-based composition of embodiment 12, wherein Z is H.-   21. The plant-based composition of embodiment 12 wherein Z is a    monovalent cation comprising sodium or potassium.-   22. The plant-based composition of embodiment 12 wherein Z is a    divalent cation comprising calcium or magnesium.-   23. The plant-based composition of embodiment 12, wherein X is H and    Z is H.-   24. The plant-based composition of embodiment 12, wherein X is H and    Z is sodium.-   25. The plant-based composition of embodiment 12, wherein X is    sodium and Z is sodium.-   26. A plant-based composition of any of embodiments 1-25 wherein the    N-acylated fatty amino acid provides an administration benefit.-   27. A plant-based composition of embodiment 26 wherein the    administration benefit is a dose-dependent administration benefit.-   28. A plant-based composition of embodiment 27 wherein the    dose-dependent administration benefit is at a dose of 100-200 mg.-   29. An plant-based composition of embodiment 26 wherein the    administration benefit includes one or more of increased absorption    of a measured component of vegetable matter, increased    bioavailability of a measured component of vegetable matter, faster    onset of action of a measured component of vegetable matter, higher    peak concentrations of a measured component of vegetable matter,    faster time to peak concentrations of a measured component of    vegetable matter, shorter duration of action, increased subjective    therapeutic efficacy, increased objective therapeutic efficacy,    improved taste, and improved mouthfeel as compared to a control    composition without the N-acylated fatty amino acid.-   30. A plant-based composition of any of embodiments 1-29 wherein the    plant-based composition is a medicinal composition.-   31. A plant-based composition of any of embodiments 1-30 wherein the    plant-based composition is a nutritional supplement.-   32. A plant-based composition of any of embodiments 1-31 including a    surfactant, detergent, azone, pyrrolidone, glycol or bile salt.-   33. A plant-based composition of any of embodiments 1-32 including a    therapeutically effective amount of vegetable matter.-   34. A plant-based composition of embodiment 33 wherein the    therapeutically effective amount treats a symptom of acquired    hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS,    AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic    lateral sclerosis (ALS), ankyloses, anxiety, arthritis, Asperger's    syndrome, asthma, atherosclerosis, autism, auto-immune diseases,    bacterial infections, bipolar disorder, bone loss, blood disorders,    brain injury/stroke, cachexia, cancer, carpal tunnel syndrome,    cerebral palsy, cervical disk disease, cervicobrachial syndrome,    chronic fatigue syndrome, chronic pain, cluster headache,    conjunctivitis, Crohn's disease, cystic fibrosis, depression,    dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy,    fever, fibromyalgia, flu, fungal infection, gastrointestinal    disorders, glaucoma, glioma, Grave's disease, heart disease    hepatitis, herpes, Huntington's disease, hypertension, impotence,    incontinence, infant mortality, inflammation, inflammatory bowel    disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause,    metabolic disorders, migraine headaches, motion sickness, MRSA,    multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail    patella syndrome, nausea and vomiting associated with cancer    chemotherapy, neuroinflammation, nicotine addiction, obesity,    obsessive compulsive disorder (OCD), pain, pancreatitis, panic    disorder, Parkinson's disease, periodontal disease, peripheral    neuropathy, phantom limb pain, poison ivy allergy, premenstrual    syndrome (PMS), proximal myotonic myopathy, post-traumatic stress    disorder (PTSD), psoriasis, Raynaud's disease, restless leg    syndrome, schizophrenia, scleroderma, septic shock, shingles herpes    zoster), sickle cell disease, seizures, sleep apnea, sleep    disorders, spinal injuries, stress, stuttering, temporomandibular    joint disorder (TMJ), tension headaches, tinnitus, Tourette's    syndrome, traumatic memories, wasting syndrome, and withdrawal.-   35. A plant-based composition of any of embodiments 1-34 including    vitamins or minerals.-   36. A plant-based composition of any of embodiments 1-34 including    vitamins and minerals.-   37. A plant-based composition of embodiments 35 or 36 wherein the    vitamins are selected from one or more of Vitamin A, Vitamin B1,    Vitamin B6, Vitamin B12, Vitamin C, Vitamin D, Vitamin E, or Vitamin    K.-   38. A plant-based composition of any of embodiments 35-36 wherein    the minerals are selected from one or more of calcium, chromium,    iodine, iron, magnesium, selenium or zinc.-   39. An oral formulation including a plant-based composition of any    of embodiments 1-38.-   40. An oral formulation of embodiment 39 wherein the oral    formulation is swallowable or chewable.-   41. An oral formulation of embodiment 39 or 40 wherein the oral    formulation is liquid or solid.-   42. An oral formulation of any of embodiments 39-41 wherein the oral    formulation is a solution, suspension, or spray.-   43. An oral formulation of any of embodiments 39-41 wherein the oral    formulation is a tablet, capsule or sachet.-   44. An oral formulation of any of embodiments 39-43 wherein the oral    formulation is flavored.-   45. A method of preparing an oral formulation of cannabis having a    faster onset of action, wherein the method comprises adding an    absorption enhancer to the oral formulation of cannabis and wherein    the oral formulation of cannabis has a faster onset of action than    an oral formulation of cannabis without an absorption enhancer.-   46. The method of embodiment 45, wherein the absorption enhancer is    an N-acylated fatty amino acid or a salt thereof.-   47. The method of embodiment 45 or 46, wherein the N-acylated fatty    amino acid or a salt thereof comprises

-    wherein X and Z are independently H, a monovalent cation, a    divalent metal cation, or an organic cation.-   48. The method of any one of embodiments 45-47, wherein the    N-acylated fatty amino acid is selected from    monosodium-N-salicyloyl-8-aminocaprylate,    disodium-N-salicyloyl-8-aminocaprylate, and    N-(salicyloyl)-8-aminocaprylic acid.-   49. A method of treating a subject in need thereof including    administering a therapeutically effective amount of a composition of    any of embodiments 1-39 or a formulation of any of embodiments 40-45    to the subject thereby treating the subject in need thereof.-   50. A method of embodiment 50 wherein the therapeutically effective    amount provides an effective amount, a prophylactic treatment,    and/or a therapeutic treatment.-   51. A method of reducing or eliminating one or more symptoms of a    disease or disorder in a human subject,-    wherein said method includes delivering a therapeutically effective    amount of a composition of any of embodiments 1-39 or oral    formulation of any of embodiments 40-45 to the subject, thereby    reducing or eliminating one or more symptoms of the disease or    disorder, and-    wherein said disease or disorder is acquired hypothyroidism, acute    gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related    anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral    sclerosis (ALS), ankyloses, anxiety, arthritis, Asperger's syndrome,    asthma, atherosclerosis, autism, auto-immune diseases, bacterial    infections, bipolar disorder, bone loss, blood disorders, brain    injury/stroke, cachexia, cancer, carpal tunnel syndrome, cerebral    palsy, cervical disk disease, cervicobrachial syndrome, chronic    fatigue syndrome, chronic pain, cluster headache, conjunctivitis,    Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes,    dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia,    flu, fungal infection, gastrointestinal disorders, glaucoma, glioma,    Grave's disease, heart disease hepatitis, herpes, Huntington's    disease, hypertension, impotence, incontinence, infant mortality,    inflammation, inflammatory bowel disease (IBD), insomnia, liver    fibrosis, mad cow disease, menopause, metabolic disorders, migraine    headaches, motion sickness, MRSA, multiple sclerosis (MS), muscular    dystrophy, mucosal lesions, nail patella syndrome, nausea and    vomiting associated with cancer chemotherapy, neuroinflammation,    nicotine addiction, obesity, obsessive compulsive disorder (OCD),    osteoporosis, osteopenia, pain, pancreatitis, panic disorder,    Parkinson's disease, periodontal disease, peripheral neuropathy,    phantom limb pain, poison ivy allergy, premenstrual syndrome (PMS),    proximal myotonic myopathy, post-traumatic stress disorder (PTSD),    psoriasis, Raynaud's disease, restless leg syndrome, schizophrenia,    scleroderma, septic shock, shingles herpes zoster), sickle cell    disease, seizures, sleep apnea, sleep disorders, spinal injuries,    stress, stuttering, temporomandibular joint disorder (TMJ), tension    headaches, tinnitus, Tourette's syndrome, traumatic memories,    wasting syndrome, or withdrawal syndrome.

EXAMPLES

Oral cannabinoid dosage form providing improved bioavailability andshortened time to onset of effect. Considering the wealth of medicalconditions potentially benefiting from cannabis therapy, a significantunmet need exists for a faster-acting product that provides improvedbioavailability in an oral format. Current oral cannabis productsinclude edibles and traditional pharmaceutical dosage forms that arechallenged by low bioavailability, and prolonged time to onset ofaction. The present disclosure addresses the shortcomings of all of thecurrently available oral cannabis products to provide an improved timeto onset of effect and improved bioavailability.

Example 1

Exemplary Formulations. Solution formulation. Cannabis and one or moreN-acylated fatty amino acids are combined in an aqueous/organic solventmixture. The resulting blend is stirred vigorously for an hour. Ifsolution is incomplete, a surfactant can be added and stirring can becontinued to prepare the final formulation.

Suspension formulation. Cannabis and one or more N-acylated fatty aminoacids are combined in water, an aqueous/organic solvent mixture or anorganic solvent mixture. The resulting blend can be stirred to effectsuspension.

Solution formulation. Cannabis and one or more absorption enhancingagents are combined in an aqueous/organic solvent mixture. The resultingblend is stirred vigorously for an hour. If solution is incomplete, asurfactant can be added and stirring can be continued to prepare thefinal formulation.

Suspension formulation. Cannabis and one or more absorption enhancingagents are combined in water, an aqueous/organic solvent mixture or anorganic solvent mixture. The resulting blend can be stirred to effectsuspension.

Gelcap composition. A suspension formulation or solution formulation canbe filled into a gelcap to contain up to 1 g of cannabis. The gelcap canbe treated with an enteric coat or used without a coating.

Tablet/capsule composition. The solution formulation and the suspensionformulation can be dried by evaporation, lyophilization, or spraydrying. The resultant dry product can be combined with tabletingexcipients and compressed into tablets or caplets to contain up to 1 gof cannabis. Alternatively, the dry product can be filled into capsules.

Example 2

Onset and duration of action of orally administered cannabis/SNACcomposition. This study was designed to assess the utility of SNAC inenabling a rapid-acting oral form of cannabis.

Selection of Participants. Six study participants were recruited toingest cannabis compositions and record the onset, duration, andintensity of cannabis-induced euphoria and/or dysphoria. Studyparticipants took part in two separate tests: 1) use of a controlsubstance, which included liquid cannabis extract dissolved in aqueousethanol, and 2) use of a test substance, which included the liquidcannabis extract dissolved in aqueous ethanol, as well as SNAC.

Formulations. The selected cannabis concentrate is commerciallyavailable and was provided to participants in an ethanol solution. Theconcentrate contains 8 mg THC per dose. It was selected because itcontains a high percentage of THC, which provides a noticeable effect onuser-reported “euphoria”. Aqueous ethanol was used as solvent because iteffectively dissolves cannabis extract, as well as SNAC.

Methods. For the Control experiment, each participant mixed the cannabisconcentrate with 15 ml (one tablespoon) of aqueous ethanol, andimmediately swallowed the mixture.

For the Test experiment, each participant mixed the cannabis concentratewith a pre-mixed solution of aqueous ethanol and 200 mg SNAC, andimmediately swallowed the dissolved mixture.

For both the Control experiment and the Test experiment, eachparticipant recorded the time of dose administration, the time of onsetof euphoria and/or dysphoria, and the observed level of euphoria and/ordysphoria in fifteen minute intervals for five hours followingadministration of the cannabis dose. Euphoria and dysphoria werereported using a scale value, in a range from 1-10. Table 1 showsdescriptions of euphoria and dysphoria levels for each scale value.

TABLE 1 Scale Values for Reporting Euphoria and Dysphoria Scale ValueDescription 0 No observed effect 1-2 Mild observed effect; possiblypsychological 3-4 Definite but mild effect 5-6 Definite substantialeffect 7-8 Strong effect 9-10 Intense effect

Results. The results shown below are the average scale values obtainedfor all six participants (also shown in FIGS. 5A and 5B).

TABLE 2 Control Experiment (n = 6) Actual Time Observed Observed Timefrom Start “Euphoria” “Dysphoria” 12:00 PM 0:00 (0-10) (0-10) 12:15 PM0:15 0.17 0.00 12:30 PM 0:30 0.50 0.00 12:45 PM 0:45 0.83 0.17  1:00 PM1:00 1.33 0.17  1:15 PM 1:15 1.67 0.50  1:30 PM 1:30 1.83 0.67  1:45 PM1:45 1.83 0.83  2:00 PM 2:00 2.00 0.50  2:15 PM 2:15 2.17 0.50  2:30 PM2:30 1.83 0.33  2:45 PM 2:45 1.67 0.33  3:00 PM 3:00 2.17 0.33  3:15 PM3:15 1.33 0.17  3:30 PM 3:30 1.17 0.00  3:45 PM 3:45 1.00 0.00  4:00 PM4:00 1.00 0.00  4:15 PM 4:15 0.83 0.00  4:30 PM 4:30 0.67 0.00  4:45 PM4:45 0.50 0.00  5:00 PM 5:00 0.17 0.00

TABLE 3 Test Experiment (n = 6) Time Actual from Observed Observed TimeStart “Euphoria” “Dysphoria” 12:00 PM 0:00 (0-10) (0-10) 12:03 PM 0:033.83 0.67 12:15 PM 0:15 3.83 0.67 12:30 PM 0:30 4.67 0.83 12:45 PM 0:454.33 0.50  1:00 PM 1:00 4.33 0.50  1:15 PM 1:15 3.67 0.67  1:30 PM 1:302.00 0.17  1:45 PM 1:45 1.83 0.17  2:00 PM 2:00 1.83 0.00  2:15 PM 2:151.67 0.00  2:30 PM 2:30 1.83 0.00  2:45 PM 2:45 1.50 0.00  3:00 PM 3:001.33 0.17  3:15 PM 3:15 1.33 0.17  3:30 PM 3:30 1.50 1.00  3:45 PM 3:451.33 0.00  4:00 PM 4:00 0.50 0.00  4:15 PM 4:15 0.17 0.00  4:30 PM 4:300.17 0.00  4:45 PM 4:45 0.00 0.00  5:00 PM 5:00 0.00 0.00

Onset: All six participants reported euphoria within five minutes ofingesting the cannabis/SNAC formulation (Test), with the time of onsetranging between two and five minutes. In contrast, the first time-pointof euphoria reported by participants after ingestion of thecannabis-only formulation (Control) was fifteen minutes post-ingestion,with the time of onset ranging between fifteen minutes and one hour,fifteen minutes (see FIGS. 6A-6F for individual participant results). Byfifteen minutes post-ingestion, the average reported euphoria scalevalue was 3.8 for the cannabis/SNAC formulation (Test). In contrast,fifteen minutes after ingestion of the cannabis-only formulation(Control), the average reported euphoria scale value was 0.17 (see FIGS.5A-5B for averages at each time-point).

Intensity: The average peak euphoria scale value after ingestion of thecannabis/SNAC formulation (Test) was 4.7, which occurred thirty minutespost-ingestion. In contrast, the highest average euphoria scale valueafter ingestion of the cannabis-only formulation (Control) was 2.2,which was at the two hour, fifteen minute time-point (see FIGS. 5A and5B). Therefore, ingestion of the cannabis/SNAC formulation led to ahigher peak intensity of euphoria, which occurred an average of one hourand forty-five minutes faster than when the cannabis-only formulationwas ingested. The intensity of observed dysphoria was minimal for boththe Test and Control, with a peak average scale value of 0.83 for bothexperiments.

Duration: The results indicate that the addition of an absorptionenhancer does not shorten the action of cannabis.

In summary, adding an absorption enhancer, such as SNAC, in an oraldosage formulation of cannabis provides faster onset of action andhigher intensity of action at peak activity level of cannabis. Moreover,the absorption enhancer has no effect on the duration of action ofcannabis.

Example 3

Onset and duration of action of orally administered cannabis/SNACcomposition at a low SNAC dose. This study was designed to assess theutility of SNAC in enabling a rapid-acting oral form of cannabis at alow dose.

Selection of Participants. Three study participants were recruited toingest cannabis compositions and record the onset, duration, andintensity of cannabis-induced euphoria and/or dysphoria. Studyparticipants took part in two separate tests: 1) use of a controlsubstance, which included liquid cannabis extract dissolved in aqueousethanol, and 2) use of a test substance, which included the liquidcannabis extract dissolved in aqueous ethanol, as well as SNAC.

Formulations. The selected cannabis concentrate is commerciallyavailable and was provided to participants in an ethanol solution. Theconcentrate contains 8 mg THC per dose. It was selected because itcontains a high percentage of THC, which provides a noticeable effect onuser-reported “euphoria”. Aqueous ethanol was used as solvent because iteffectively dissolves cannabis extract, as well as SNAC.

Methods. For the Control experiment, each participant mixed the cannabisconcentrate with 15 ml (one tablespoon) of aqueous ethanol, andimmediately swallowed the mixture.

For the Test experiment, each participant mixed the cannabis concentratewith a pre-mixed solution of aqueous ethanol and 100 mg SNAC, andimmediately swallowed the dissolved mixture.

For both the Control experiment and the Test experiment, eachparticipant recorded the time of dose administration, the time of onsetof euphoria and/or dysphoria, and the observed level of euphoria and/ordysphoria in fifteen minute intervals for five hours followingadministration of the cannabis dose. Euphoria and dysphoria werereported using a scale value, in a range from 1-5. Table 1 showsdescriptions of euphoria and dysphoria levels for each scale value.

Results. The results are combined with the data from Example 2 and arereported for all participants in FIG. 7.

Onset: All three participants reported euphoria within five minutes ofingesting the cannabis/SNAC formulation (Test), with the time of onsetranging between two and five minutes. In contrast, the first time-pointof euphoria reported by participants after ingestion of thecannabis-only formulation (Control) was fifteen minutes post-ingestion,with the time of onset ranging between fifteen minutes and one hour,fifteen minutes. By fifteen minutes post-ingestion, the average reportedeuphoria scale value was 3.0 for the cannabis/SNAC formulation (Test).In contrast, fifteen minutes after ingestion of the cannabis-onlyformulation (Control), the average reported euphoria scale value was0.25.

Intensity: The average peak euphoria scale value after ingestion of thecannabis/SNAC formulation (Test) was 3.4, which occurred thirty minutespost-ingestion. In contrast, the highest average euphoria scale valueafter ingestion of the cannabis-only formulation (Control) was 2.2,which was at the two hour, fifteen minute time-point. Compared toExample 2 where the SNAC dose was 200 mg, the participants in Example 3ingested only 100 mg of SNAC combined with the same quantity of cannabisused in Example 2. This reduced quantity of SNAC resulted in a reducedcannabis effect demonstrating a clear dose-response relationship betweenobserved cannabis effect (euphoria) and SNAC dose. Consistent withExample 2, ingestion of the cannabis/SNAC formulation led to a higherpeak intensity of euphoria, which occurred an average of one hour andforty-five minutes faster than when the cannabis-only formulation wasingested.

Duration: The results indicate that the addition of an absorptionenhancer does not shorten the action of cannabis.

In summary, adding an absorption enhancer, such as SNAC, in an oraldosage formulation of cannabis provides faster onset of action andhigher intensity of action at peak activity level of cannabis. Moreover,the absorption enhancer has no effect on the duration of action ofcannabis. The varying quantity of SNAC produces a clear dose-responserelationship between observed cannabis effect (euphoria) and SNAC dose.

As will be understood by one of ordinary skill in the art, eachembodiment disclosed herein can comprise, consist essentially of orconsist of its particular stated element, step, ingredient or component.Thus, the terms “include” or “including” should be interpreted torecite: “comprise, consist of, or consist essentially of.” As usedherein, the transition term “comprise” or “comprises” means includes,but is not limited to, and allows for the inclusion of unspecifiedelements, steps, ingredients, or components, even in major amounts. Thetransitional phrase “consisting of” excludes any element, step,ingredient or component not specified. The transition phrase “consistingessentially of” limits the scope of the embodiment to the specifiedelements, steps, ingredients or components and to those that do notmaterially affect the embodiment. As used herein, a material effectwould cause a statistically-significant reduction in an administrationbenefit when assessed in an experimental protocol disclosed herein.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. When further clarity is required, the term “about” has themeaning reasonably ascribed to it by a person skilled in the art whenused in conjunction with a stated numerical value or range, i.e.denoting somewhat more or somewhat less than the stated value or range,to within a range of ±20% of the stated value; ±19% of the stated value;±18% of the stated value; ±17% of the stated value; ±16% of the statedvalue; ±15% of the stated value; ±14% of the stated value; ±13% of thestated value; ±12% of the stated value; ±11% of the stated value; ±10%of the stated value; ±9% of the stated value; ±8% of the stated value;±7% of the stated value; ±6% of the stated value; ±5% of the statedvalue; ±4% of the stated value; ±3% of the stated value; ±2% of thestated value; or ±1% of the stated value.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents, printedpublications, journal articles and other written text throughout thisspecification (referenced materials herein). Each of the referencedmaterials are individually incorporated herein by reference in theirentirety for their referenced teaching.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

The particulars shown herein are by way of example and for purposes ofillustrative discussion of the preferred embodiments of the presentinvention only and are presented in the cause of providing what isbelieved to be the most useful and readily understood description of theprinciples and conceptual aspects of various embodiments of theinvention. In this regard, no attempt is made to show structural detailsof the invention in more detail than is necessary for the fundamentalunderstanding of the invention, the description taken with the drawingsand/or examples making apparent to those skilled in the art how theseveral forms of the invention may be embodied in practice.

Definitions and explanations used in the present disclosure are meantand intended to be controlling in any future construction unless clearlyand unambiguously modified in the following examples or when applicationof the meaning renders any construction meaningless or essentiallymeaningless. In cases where the construction of the term would render itmeaningless or essentially meaningless, the definition should be takenfrom Webster's Dictionary, 3rd Edition or a dictionary known to those ofordinary skill in the art, such as the Oxford Dictionary of Biochemistryand Molecular Biology (Ed. Anthony Smith, Oxford University Press,Oxford, 2004).

What is claimed is:
 1. A fast-acting plant-based composition formulated for oral delivery comprising (i) THC and/or CBD and (ii) N-[8-(2-hydroxybenzoyl) amino] caprylate.
 2. A fast-acting plant-based composition formulated for oral delivery comprising (i) vegetable matter with an aqueous solubility of less than 0.1 mg/ml and (ii) N-[8-(2-hydroxybenzoyl) amino] caprylate.
 3. A plant-based composition comprising vegetable matter and an N-acylated fatty amino acid or a salt thereof.
 4. A plant-based composition comprising a botanical product and an N-acylated fatty amino acid or a salt thereof.
 5. A plant-based composition of claim 3 wherein the vegetable matter is derived from Calophyllum brasiliense, Calophyllum caledonicum, Calophyllum inophyllum, Calophyllum soulattri, Uncaria tomentosa, Thymus vulgaris, Matricaria recutita, Salix alba, Calendula officinalis, Usnea barbata, Ligusticum porterii-osha, Gaultheria procumbens, Camellia sinensis, Vaccinium myrtillus, Melissa officinalis, Allium sativum, Camellia sinensis, Krameria triandra, Punica granatum, Viburnum plicatum, Nicotiana tabacum, Duboisia hopwoodii, Asclepias syriaca, Curcuma longa, Cannabis sativa, Cannabis indica, Cannabis ruderalis and/or Acer spp, or an extract thereof.
 6. A plant-based composition of claim 3 wherein the vegetable matter is derived from cannabis.
 7. A plant-based composition of claim 3 wherein the vegetable matter is derived from Cannabis sativa, Cannabis ruderalis, or Cannabis indica.
 8. A plant-based composition of claim 3 comprising a cannabis extract.
 9. A plant-based composition of claim 3 comprising cannabinoids.
 10. A plant-based composition of claim 3 comprising Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerolic acid, cannabidiolic acid (CBDA), Cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarinic acid (THCVA) and/or mixtures thereof.
 11. A plant-based composition of claim 3 comprising flavonoid compounds, terpenes, or terpenoids.
 12. A plant-based composition of claim 3 wherein the N-acylated fatty amino acid comprises one or more of Compounds I-XXXV (FIG. 3), or Compounds a-r (FIG. 4).
 13. A plant-based composition of claim 3 wherein the N-acylated fatty amino acid comprises monosodium-N-salicyloyl-8-aminocaprylate, disodium-N-salicyloyl-8-aminocaprylate, or N-(salicyloyl)-8-aminocaprylic acid.
 14. A plant-based composition of claim 3 wherein the N-acylated fatty amino acid or a salt thereof comprises

wherein X and Z are independently H, a monovalent cation, a divalent metal cation, or an organic cation.
 15. The plant-based composition of claim 14, wherein the monovalent cation is sodium or potassium.
 16. The plant-based composition of claim 14, wherein the metal cation is calcium or magnesium.
 17. The plant-based composition of claim 14, wherein the organic cation is ammonium or tetramethylammonium.
 18. The plant-based composition of claim 14, wherein X is H.
 19. The plant-based composition of claim 14, wherein X is a monovalent cation comprising sodium or potassium.
 20. The plant-based composition of claim 14, wherein X is a divalent metal cation comprising calcium or magnesium.
 21. The plant-based composition of claim 14, wherein X is an organic cation comprising ammonium or tetramethylammonium.
 22. The plant-based composition of claim 14, wherein Z is H.
 23. The plant-based composition of claim 14 wherein Z is a monovalent cation comprising sodium or potassium.
 24. The plant-based composition of claim 14 wherein Z is a divalent cation comprising calcium or magnesium.
 25. The plant-based composition of claim 14, wherein X is H and Z is H.
 26. The plant-based composition of claim 14, wherein X is H and Z is sodium.
 27. The plant-based composition of claim 14, wherein X is sodium and Z is sodium.
 28. A plant-based composition of claim 3 wherein the N-acylated fatty amino acid or salt thereof provides an administration benefit.
 29. A plant-based composition of claim 28 wherein the administration benefit is a dose-dependent administration benefit.
 30. A plant-based composition of claim 29 wherein the dose-dependent administration benefit is at a dose of 100-200 mg.
 31. An plant-based composition of claim 28 wherein the administration benefit comprises one or more of increased absorption of a measured component of vegetable matter, increased bioavailability of a measured component of vegetable matter, faster onset of action of a measured component of vegetable matter, higher peak concentrations of a measured component of vegetable matter, faster time to peak concentrations of a measured component of vegetable matter, shorter duration of action, increased subjective therapeutic efficacy, increased objective therapeutic efficacy, improved taste, and improved mouthfeel as compared to a control composition without the N-acylated fatty amino acid.
 32. A plant-based composition of claim 3 wherein the plant-based composition is a medicinal composition.
 33. A plant-based composition of claim 3 wherein the plant-based composition is a nutritional supplement.
 34. A plant-based composition of claim 3 comprising a botanical product.
 35. A plant-based composition of claim 3 comprising a surfactant, detergent, azone, pyrrolidone, glycol or bile salt.
 36. A plant-based composition of claim 3 comprising a therapeutically effective amount of vegetable matter.
 37. A plant-based composition of claim 36 wherein the therapeutically effective amount treats a symptom of acquired hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ankyloses, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, auto-immune diseases, bacterial infections, bipolar disorder, bone loss, blood disorders, brain injury/stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disk disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headache, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infection, gastrointestinal disorders, glaucoma, glioma, Grave's disease, heart disease hepatitis, herpes, Huntington's disease, hypertension, impotence, incontinence, infant mortality, inflammation, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, metabolic disorders, migraine headaches, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine addiction, obesity, obsessive compulsive disorder (OCD), pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral neuropathy, phantom limb pain, poison ivy allergy, premenstrual syndrome (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), psoriasis, Raynaud's disease, restless leg syndrome, schizophrenia, scleroderma, septic shock, shingles herpes zoster), sickle cell disease, seizures, sleep apnea, sleep disorders, spinal injuries, stress, stuttering, temporomandibular joint disorder (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome, and withdrawal.
 38. A plant-based composition of claim 3 comprising vitamins or minerals.
 39. A plant-based composition of claim 3 comprising vitamins and minerals.
 40. A plant-based composition of claim 38 or 39 wherein the vitamins are selected from one or more of Vitamin A, Vitamin B1, Vitamin B6, Vitamin B12, Vitamin C, Vitamin D, Vitamin E, or Vitamin K.
 41. A plant-based composition of claim 38 or 39 wherein the minerals are selected from one or more of calcium, chromium, iodine, iron, magnesium, selenium and/or zinc.
 42. An oral formulation comprising a plant-based composition of claim
 3. 43. An oral formulation of claim 42 wherein the oral formulation is swallowable or chewable.
 44. An oral formulation of claim 42 wherein the oral formulation is liquid or solid.
 45. An oral formulation of claim 42 wherein the oral formulation is a solution, suspension, or spray.
 46. An oral formulation of claim 42 wherein the oral formulation is a tablet, capsule or sachet.
 47. An oral formulation of claim 42 wherein the oral formulation is flavored.
 48. A method of preparing an oral formulation of cannabis having a faster onset of action, wherein the method comprises adding an absorption enhancer to the oral formulation of cannabis and wherein the oral formulation of cannabis has a faster onset of action than an oral formulation of cannabis without an absorption enhancer.
 49. The method of claim 48, wherein the absorption enhancer is an N-acylated fatty amino acid or a salt thereof.
 50. The method of claim 49, wherein the N-acylated fatty amino acid or a salt thereof comprises

wherein X and Z are independently H, a monovalent cation, a divalent metal cation, or an organic cation.
 51. The method of claim 49, wherein the N-acylated fatty amino acid is selected from monosodium-N-salicyloyl-8-aminocaprylate, disodium-N-salicyloyl-8-aminocaprylate, and N-(salicyloyl)-8-aminocaprylic acid.
 52. A method of treating a subject in need thereof including administering a therapeutically effective amount of a composition of claim 3 to the subject thereby treating the subject in need thereof.
 53. A method of claim 52 wherein the therapeutically effective amount provides an effective amount, a prophylactic treatment, and/or a therapeutic treatment.
 54. A method of reducing or eliminating one or more symptoms of a disease or disorder in a human subject, wherein said method includes delivering a therapeutically effective amount of a composition of claim 3 to the subject, thereby reducing or eliminating one or more symptoms of the disease or disorder, and wherein said disease or disorder is acquired hypothyroidism, acute gastritis, addiction, ADHD, agoraphobia, AIDS, AIDS-related anorexia, alcoholism, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ankyloses, anxiety, arthritis, Asperger's syndrome, asthma, atherosclerosis, autism, auto-immune diseases, bacterial infections, bipolar disorder, bone loss, blood disorders, brain injury/stroke, cachexia, cancer, carpal tunnel syndrome, cerebral palsy, cervical disk disease, cervicobrachial syndrome, chronic fatigue syndrome, chronic pain, cluster headache, conjunctivitis, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, dystonia, eating disorders, eczema, epilepsy, fever, fibromyalgia, flu, fungal infection, gastrointestinal disorders, glaucoma, glioma, Grave's disease, heart disease hepatitis, herpes, Huntington's disease, hypertension, impotence, incontinence, infant mortality, inflammation, inflammatory bowel disease (IBD), insomnia, liver fibrosis, mad cow disease, menopause, metabolic disorders, migraine headaches, motion sickness, MRSA, multiple sclerosis (MS), muscular dystrophy, mucosal lesions, nail patella syndrome, nausea and vomiting associated with cancer chemotherapy, neuroinflammation, nicotine addiction, obesity, obsessive compulsive disorder (OCD), osteoporosis, osteopenia, pain, pancreatitis, panic disorder, Parkinson's disease, periodontal disease, peripheral neuropathy, phantom limb pain, poison ivy allergy, premenstrual syndrome (PMS), proximal myotonic myopathy, post-traumatic stress disorder (PTSD), psoriasis, Raynaud's disease, restless leg syndrome, schizophrenia, scleroderma, septic shock, shingles herpes zoster), sickle cell disease, seizures, sleep apnea, sleep disorders, spinal injuries, stress, stuttering, temporomandibular joint disorder (TMJ), tension headaches, tinnitus, Tourette's syndrome, traumatic memories, wasting syndrome, or withdrawal syndrome. 